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Review

Post-Operative Adhesions: A Comprehensive Review of Mechanisms

by
Ali Fatehi Hassanabad
1,
Anna N. Zarzycki
1,
Kristina Jeon
2,
Justin F. Deniset
1,3 and
Paul W. M. Fedak
1,*
1
Section of Cardiac Surgery, Department of Cardiac Sciences, Libin Cardiovascular Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 2N9, Canada
2
Department of Anesthesiology and Pain Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2R7, Canada
3
Department of Physiology and Pharmacology, University of Calgary, Calgary, AB T2N 1N4, Canada
*
Author to whom correspondence should be addressed.
Biomedicines 2021, 9(8), 867; https://doi.org/10.3390/biomedicines9080867
Submission received: 6 June 2021 / Revised: 27 June 2021 / Accepted: 15 July 2021 / Published: 22 July 2021
(This article belongs to the Section Molecular and Translational Medicine)
Browse Figure
Versions Notes

Abstract

:
Post-surgical adhesions are common in almost all surgical areas and are associated with significant rates of morbidity, mortality, and increased healthcare costs, especially when a patient requires repeat operative interventions. Many groups have studied the mechanisms driving post-surgical adhesion formation. Despite continued advancements, we are yet to identify a prevailing mechanism. It is highly likely that post-operative adhesions have a multifactorial etiology. This complex pathophysiology, coupled with our incomplete understanding of the underlying pathways, has resulted in therapeutic options that have failed to demonstrate safety and efficacy on a consistent basis. The translation of findings from basic and preclinical research into robust clinical trials has also remained elusive. Herein, we present and contextualize the latest findings surrounding mechanisms that have been implicated in post-surgical adhesion formation.

Graphical Abstract

1. Introduction

Post-operative adhesions are pathological bonds that form between surfaces within body cavities, and range from a thin film of connective tissue to thick fibrous bridges that contain blood vessels and nerve tissue [1]. Previous publications describe post-surgical adhesions as scar tissue, whereas current understanding reflects their dynamic and regenerating nature, which can be characterized by distinct cellular and immune responses [2,3,4]. Post-operative adhesion formation following pelvic, peritoneal, and thoracic surgeries is a common response to tissue trauma and ischemia. It has been reported that pathologic adhesions develop after 95% of all operations, regardless of procedure or location in the body [5]. These fibrous bonds can directly or indirectly cause complications including severe chronic pain, organ dysfunction, and the increased need for “redo surgeries”, which may include surgeries to release the adhesions themselves (a procedure known as adhesiolysis).
Post-surgical adhesions can prolong operative time in repeat surgeries, but can also increase the risk of mortality, as well as conferring major financial burden on the healthcare system [6,7,8,9,10,11]. The treatment of post-operative adhesions costs the US healthcare system over USD 2.5 billion annually, while complications related to post-surgical adhesions results in nearly one million additional days of inpatient care annually [12]. This staggering estimate of cost excludes expenditures such as imaging, diagnostic, and laboratory tests, ambulance and transport service, long-term morbidity costs, mental health implications, or the societal cost of early mortality [11]. Thus, there is an unmet clinical need for the development of safe and effective therapeutic options that can be used to mitigate post-operative adhesion formation. Success in such an endeavor requires a better understanding of the different mechanisms that contribute to post-surgical adhesions. Herein, we comprehensively summarize, contextualize, and critically appraise the existing data pertaining to the mechanisms that have been identified to drive post-surgical adhesion formation.

2. Clinical Significance of Post-Surgical Adhesions

2.1. Pelvic and Abdominal Adhesions

Peritoneal adhesions are commonplace after abdominal surgery, which is the most common cause of post-surgical adhesions where 70–90% of them have been attributed to a previous surgery [13,14]. It has also been shown that in 10 years following a pelvic or abdominal surgery, 35% of patients were readmitted a mean of 2.1 times for a disorder directly or potentially related to adhesions [7]. Post-surgical abdominal and pelvic adhesions also have serious clinical implications, including small bowel obstruction [15] and an increased risk profile at the time of repeat surgeries due to hemorrhage, perforation, reduced surgical exposure, and prolonged operative times [16,17,18].

2.2. Thoracic Adhesions

Much of the current literature on post-surgical adhesions relates to the consequences and potential prevention techniques for pelvic or peritoneal adhesions. However, post-cardiothoracic surgery adhesions are becoming more recognized as the incidence of redo surgeries and subsequent adhesion-related complications increase. Indeed, 6–17% of all coronary artery bypass and valve surgeries are reoperations [19,20]. Post-operative adhesions substantially lengthen surgical times and increase the risks of injury to the heart, lungs, and great vessels during sternal re-entry. Patients with congenital heart disease are likely to require several redo cardiac operations over their lifetime, where up to 33% of all pediatric and congenital heart surgeries are reoperations [21].
Pericardial post-surgical adhesion formation has been mainly studied in animal models [22]. Closure of the pericardium after surgery is recommended as it offers protection for the heart and great vessels during reoperation. However, this can be challenging as there is usually edematous enlargement of the intra-thoracic structures. There also exists a risk of the pericardium compressing the heart and any bypass grafts, which has led many surgeons to leave the pericardium open. Complications of intra-thoracic and cardiac adhesions include life-threatening hemorrhage during redo-sternotomy, right ventricular dysfunction, and decreased coronary artery bypass graft patency [23,24]. Repeat cardiac procedures on hearts with high levels of adhesions also increase operative time [23].

3. Mechanisms Driving Post-Surgical Adhesion Formation

Post-surgical adhesion formation involves three core processes: (A) inhibition of the fibrinolytic and extracellular matrix degradation systems, (B) the induction of an inflammatory response involving the production of cytokines and transforming growth factor-β (TGF-β), and (C) induction of tissue hypoxia, leading to increased expression of vascular endothelial growth factor (VEGF) [25]. From studies on peritoneal adhesions, we know the cellular components of adhesions: macrophages, eosinophils, red blood cells, tissue debris, mast cells, and fibroblasts, contained within the deposited matrix. As adhesions mature, their cell population changes: from days one to three, cells are mainly polymorphonuclear cells (PMN) leukocytes; whereas between days five to seven fibroblasts predominate [26]. Understanding how cells and factors contribute to the formation of adhesions is key for developing successful preventative strategies. Indeed, studies have aimed to elucidate key markers that are dysregulated and lead to adhesions. Factors that have been identified include those important for the regulation of inflammatory and immune responses, tissue remodeling, and angiogenesis and are briefly detailed in Table 1 and Table 2.

3.1. Fibrin

Cellular insult results in an outpouring of fibrin and subsequent fibrinolysis [23]. It is thought that the insult causes hypoxia and the release of reactive oxygen species (ROS) [27], which lead to inflammation and activation of the coagulation cascade where fibrin formation plays a key role [2]. Specifically, the activation of the coagulation cascade increases the production of thrombin, which is a key activator of fibrin. Fibrin production and fibrinolysis are part of the physiologic process that is necessary for tissue healing. Once the balance between fibrin production and fibrinolysis becomes compromised pathological adhesion formation occurs.
Deposition of fibrin monomers develop a polymeric matrix within which fibroblasts can adhere and produce components of extracellular matrix (ECM), setting the stage for mature adhesion formation. Within this fibrinous matrix, polymorphonuclear cells (PMN), macrophages, and mesothelial cells migrate, proliferate, and differentiate. These cells release a variety of substances including plasminogen system components, arachidonic acid metabolites, ROS, cytokines, and growth factors, which have been shown to modulate adhesion formation at different stages [28,29].
Post-operative hypoxia is common in surgical patients [30], and fibrinolysis has been shown to be decreased in hypoxic conditions [31,32,33]. Plasminogen activator inhibitors (PAIs) can prevent PAs from activating plasmin, leading to compromised fibrinolytic activity [34]. Surgery has also been shown to increase levels of PAIs [35]. In rats, tissue and plasma decreases in tPA and increases in PAI-1 have been reported to parallel the development of peritoneal adhesions [36]. The balance between fibrin deposition and degradation is critical in distinguishing between normal healing and pathological adhesion formation, where the persistence of fibrin eventually serves as a scaffold for fibroblasts and capillary in-growth, establishing more permanent connections.

3.2. Cellular and Immune Mechanisms

Serum-derived and soluble factors produced by platelets and inflammatory immune cells act as a network of highly active substances that initiate the healing process [29]. We know that platelets, inflammatory/immune cells, resident fibroblasts, and mesothelial cells lining body cavities are key contributors to adhesion formation. The recruitment of inflammatory and immune-related cells, such as macrophages, neutrophils, T-cells, and mast cells is facilitated by adhesions molecules and ECM components, including fibronectin and vitronectin [37]. Collectively, these cell types and the mediators they release regulate the inflammatory response, cellular migration, proliferation, angiogenesis, and tissue remodeling that controls the shift from wound healing to adhesion formation [37,38].

3.2.1. The Mesothelium

The serous membranes of the peritoneal, pleural, and pericardial cavities are from a similar embryological origin and are lined with an epithelial monolayer with microvilli, also known as the mesothelium. Mesothelial cells synthesize and secrete lubricants, including glycosaminoglycans and surfactant which prevent friction and the formation of adhesions [39]. Upon insult, mesothelial cells take on a profibrotic phenotype, secreting inflammatory mediators, chemokines, growth factors, and ECM components that contribute to coagulation, fibrinolysis, and immune cell recruitment [40,41]. More recent work has demonstrated the mesothelial-to-mesenchymal transition (MMT) to be an important driver for adhesion production [42]. Pro-inflammatory cytokines TGF-β1 and IL-6 have been found to play an important role in stimulation of peritoneal MMT. Blocking IL-6 and TGF-β1 is associated with the inhibition of extracellular signal-regulated kinase (ERK) 1/2 [43]. The capability of mesothelial cells to undergo MMT following stimulation [44] positions them as a likely source of fibrogenic myofibroblasts, therefore playing important roles in adhesion formation [40].
Mesothelial cells are loosely attached to the basement membrane and can be easily detached even with slight trauma [45]. Following traumatic insult in the peritoneum, regional mesothelial cells are lost, disrupting the smooth epithelial monolayer. New mesothelial cells are recruited by a unique subset of post-operative intraperitoneal macrophages. These mesothelial cells form small islands in response to macrophage-secreted mediators and cytokines, which proliferate into sheets of mesothelial re-mesothelialization [46]. The confluence of the islands of mesothelial cells permits both large and small peritoneal injuries to heal in the same amount of time [47]. Similar to observations in the peritoneum, the detachment of pericardial mesothelial cells appears to be critical due to an observed decrease in fibrinolytic activity in areas with denuded mesothelial cells [22]. Mediators of the inflammatory response, such as TGF-β, have been reported to promote the detachment of pericardial mesothelial cells and the transition to a fibroblast phenotype, which promotes fibrosis [48]. Pericardial re-mesothelialization is hypothesized to stem from pre-existing floating pericardial mesothelial cells that remain in the pericardial cavity and activated mesothelial cells that are adjacent to the site of injury [24].
Some studies have shown that the mesothelium plays a protective role against adhesion formation. This protective function is thought to be due to the mesothelium existing as a frictionless surface [39,49,50,51,52]. However, there is continued debate on the extent to which mesothelial cells protect from adhesions, as earlier studies have disputed their preventative mechanism [53]. Reports of the protective role of the mesothelium suggest that removing the mesothelial layer is necessary for adhesion formation. Stripped and unprotected basement membrane is hypothesized to be the substrate for fibrin attachment between cell and organ surfaces, which is followed by fibroblast accumulation [39,51].
By lineage tracing, a recent study has demonstrated that an activated subset of mesothelial cells could be the origin for adhesions [54]. They identified mesothelin as a specific surface marker that is up-regulated by mesothelial cells participating in adhesion formation. The study also found these cells to be a necessary component of adhesion tissue in mice and humans. The same group has also recently identified that the main component of the adhesion cascade are cytoskeletal and calcium-regulating effectors, reporting that post-operative adhesions are triggered by calcium-dependent membrane bridges between mesothelial surfaces in the early stages after surgery [55]. These findings suggest that membrane protrusion and fusion between mesothelial surfaces may be the early event that drives post-surgical adhesion formation, while fibroblasts and immune cells likely modulate and perpetuate the adhesion response.

3.2.2. Fibroblasts and Myofibroblasts

In peritoneal adhesions, the initial fibrinous exudate leads to the maintenance of cellular scaffolding, which allows the migration and seeding of fibroblast-like cells [56]. Studies have shown that the deposition of sub-peritoneal fibroblasts in the ECM is required for adhesion development [47,50,57,58,59,60]. As adhesions develop, fibroblasts continue to align and organize, causing subsequent deposition of collagen and ECM material, and establishing mature, fibrous adhesions [59,61]. Fibroblast content in murine models of adhesions has been shown to increase in the second week post-trauma, followed by the development of vessel structures and connective tissues elements [62,63]. In rabbits, adhesion development is further pronounced at 3-weeks post-injury and correlates with fibroblast content [64]. Histological analysis has also shown that fibroblasts responsible for the maturation of human peritoneal adhesions are myofibroblasts that demonstrate pronounced hyperplasia and collagen production [65]. However, these findings are mostly based on animal model and histological observations, so there remains continued debate on the early mechanisms driving adhesion formation.
Myofibroblasts are smooth muscle-like fibroblasts that express cytoskeletal proteins, such as α-smooth muscle actin (α-SMA) [66]. Fibroblasts in adhesions can develop an irreversible myofibroblast phenotype, overexpressing type I and III collagen, matrix metalloproteinase-1 (MMP-1), tissue inhibitor of metalloproteinase-1 (TIMP-1), fibronectin, VEGF, cyclooxygenase-2 (COX-2) [67] and TGF-β [68,69,70,71,72,73]. Intraperitoneal adhesions have increased α-SMA protein expression in adhesion-resident myofibroblasts, indicating increased cellular activity and a profibrotic response [74]. Other literature suggests that myofibroblast metaplasia may be a potential a source for adhesion formation [75].
Studies have identified that myofibroblast activation and ECM protein production and remodeling by fibroblasts are important mechanisms by which mild adhesions transition to dense, fibrous adhesions [22,76]. Fibroblasts and myofibroblasts secrete substantial amounts of ECM including fibronectin, hyaluronic acid, glycosaminoglycans, and proteoglycans [56]. Furthermore, myofibroblasts are stimulated by the pro-inflammatory and profibrotic growth factor TGF-β, which increases myofibroblast migration and activation [77]. Targeting the fibroblast-mediated mechanism of adhesion formation and maintenance may allow for more precise and targeted therapeutics.

3.2.3. Macrophages

At 24 h post-trauma, macrophages compose the inflammatory cell population at the site of injury [78] and have been identified in long-lasting adhesions (>12 months) collected from abdominal surgery patients [79]. Conversely, a recent study has shown that although the recruitment of monocytes was induced by activated macrophages through the release of monocyte chemo-attractant protein (MCP), the number of accumulated macrophages was markedly decreased throughout the adhesive time course [41]. Nevertheless, since macrophages are capable of secreting PA, PAI, interleukin 1 (IL-1), IL-6, and tumor necrosis factor-alpha (TNFα) among others, they are thought to be fundamental in triggering adhesion formation and may play a role in adhesion maintenance [80,81,82]. Recently, PA and PAI-1 have been identified as chemo-attractant for epidermal growth factor (EGF) secreting macrophages that up-regulate the EGF receptor HER1 on peritoneal mesothelial cells in a murine model [83]. This precipitates further PAI-1 secretion, leading to decreased fibrinolysis at the site of post-operative adhesion formation [83]. Additionally, macrophages recruit more inflammatory cells to the site of injury, further progressing adhesion formation [46]. Macrophages have also been reported to recruit new mesothelial cells to the site of injury [46], and exert a direct effect by influencing mesothelial cell behavior and ECM constituents [84]. In peritoneal adhesions, resident peritoneal macrophages have been implicated as key players in the immune response that leads to adhesion formation. Notably, they have a unique autocrine activation system, whereby in response to tissue damage a chemokine (CCL1) and its receptor (CCR8) are released. Inhibition of CCL1-CCR8 interactions prevents migration of macrophages and the development of peritoneal adhesions [85].
It is important to note that the function of macrophages depends on differentiation status, which can play a role in wound healing in various tissues [86]. The M1/M2 macrophage polarization paradigm has been used to delineate roles during the pathogenesis of adhesions. M2 marker expression, associated with wound healing, tissue remodeling, ECM production, and modulation of immune and inflammatory responses to tissue injury [87,88], has shown an inverse correlation with peritoneal adhesion formation in a murine model [89]. However, the role of macrophages and their differentiation status is still under debate.

3.2.4. Neutrophils

Neutrophils, the primary component of PMNs, are one of the most pronounced cell types in peritoneal cavity in the early period of peritoneal adhesion formation [45,90]. Recent observations of TGF-β+ Ly6G+ neutrophils were present in the injured serosa and submucosa at early stages of adhesion formation, indicating that neutrophils can also play a role in TGF-β secretion [91]. The production of chemokines from mesothelial and inflammatory cells, such as IL-8 and IL-1β induce the migration of neutrophils into the injured peritoneal cavity [92]. Activated mesothelial cells also directly recruit neutrophils and monocytes when subject to mechanical stress via the up-regulation of CXCL1 and MCP-1 [41].
Intraperitoneal injection of cyclophosphamide has been found to significantly reduce perioperative neutrophil counts and adhesion formation in mice [93]. Injection of polyclonal rabbit anti-rat neutrophil serum (ANS) also resulted in a reduction of neutrophil influx and significantly reduced adhesion formation in a rat model of abdominal adhesions [94]. Transient depletion of circulating neutrophils via thioglycolate-induced alteration of the immune environment has also been shown to decrease adhesion severity and burden in a murine model [41]. However, inhibition of PMN adherence has resulted in increased peritoneal adhesion formation [95,96]. A predominant product of neutrophil activity is the generation of ROS, particularly superoxide radicals. The role of oxidative stress in the pathogenesis of adhesions is well discussed in [97]. Samples of human post-operative peritoneal adhesions have demonstrated enhanced nitrotyrosine levels, commonly known as the markers of ROS [98]. Of note, the presence of ROS and ROS-sensitive transcription factor EGR-1 was also evident in a rodent peritoneal adhesion model [98]. Generally, ROS have been reported to have a direct cytotoxic effect on mesothelial cells and inhibit fibrinolysis via increasing the release of PAI-1 by mesothelial cells [94]. Treatment with superoxide dismutase (SOD) and catalase, scavengers of ROS, has been reported to significantly reduced adhesion formation in a rat model of post-operative peritoneal adhesions [94]. More recent research has shown that neutrophils within adhesion sites in mice undergo cell death and form neutrophil extracellular traps (NETs), networks of extracellular fibers primarily composed of DNA from neutrophils that contribute to adhesion pathogenesis [41]. These findings suggest that targeting neutrophils or mitigating its downstream mediators can have potentially anti-adhesive benefits. However, to avoid systemic adverse events, any such therapeutic must be precise.

3.2.5. T-Cells

In a murine model of peritoneal and visceral adhesions, T-lymphocytes have been detected with highest levels on the third day after insult, suggesting a potential role of the adaptive immune system [99]. T-lymphocytes have been reported to persist in quantity and quality without regard for adhesion maturity, indicating inflammatory activity even in long-lasting adhesions [79]. Furthermore, adoptive transfer and T-cell depletion experiments have revealed that adhesion formation requires the presence of CD4+ αβ T-cells as well as the production of T-cell dependent pro-inflammatory cytokines, such as IL-17 and others [100]. In a murine model of adhesion formation, selective recruitment of Tim-3+, CCR5+, CXCR3+, and IFN-γ+ cells indicate that adhesion formation is driven by the presence of a Th1 CD4+ phenotype [101]. Mice treated with neutralizing antibodies directed against IL-16, the Th1-selective CD4+ chemo-attractant, results in significantly less adhesion formation [101]. Similar results are seen in mice genetically deficient for IFN-γ [101]. Targeting Th2 and Treg cells by pirfenidone, an anti-fibrotic agent, has also been shown to prevent peritoneal adhesions in rats [102]. The characterization of adhesions as a state of chronic inflammation suggests T-cells may play a role in signaling pathways that maintain adhesions, notably through the mediating effects of IL-6 and other cytokines [79,103]. Many fibrotic tissue disorders share a common etiology of T-cell abnormalities in host defense where it has been postulated that adhesions can fall under a similar category [104]. This further prompts consideration of adhesions as a dynamic process in remodeling tissue [79].

3.2.6. Mast Cells

Mast cells were found in high concentrations in post-surgical adhesion sites [105]. As a pro-inflammatory cell, mast cells are responsible for releasing a host of factors including histamine, serotonin, cytokines, serine proteases, and chymase. Chymase, a chymotrypsin-like serine protease activates TGF-β. Mast cell-deficient mice demonstrate a significant reduction in adhesion formation [106], highlighting the importance of both mast cells and chymase in the pathophysiology of adhesions. In a post-cardiac surgery context in the hamster model, chymase inhibition has been shown to impede formation of connective tissue deposition and fibrosis [107]. Mast cells also release VEGF, an early pathogenic event that has been suggested to play a key role in adhesion formation [108].

3.3. Inflammation and Angiogenesis

An important feature of tissue repair and potential pathologic adhesion formation is the local inflammatory response induced by surgical trauma [109,110]. As outlined above, immune cells have been shown to play an important role in post-surgical adhesions. In this section, we focus on various inflammatory mediators that have been found to contribute to the formation and severity of post-operative adhesions. It is important to emphasize that the exact mechanisms by which these mediators drive adhesion formation is not fully delineated. A better understanding of their role in the pathogenesis of post-surgical adhesion formation will aid us in designing safer, more effective, and more precise preventative modalities.

3.3.1. Interleukins and Tumor Necrosis Factor-Alpha

Interleukins (ILs) have also been implicated in adhesion development. Injured tissue releases cytokines that act individually and synergistically to induce a humoral inflammatory tissue reaction in response to insult [111]. There has been limited information on the roles of IL-6, IL-8, and IL-10 in adhesions, although they have been theorized to be a mediator of cellular response to injury [29]. Certain studies have drawn direct correlations between cytokine levels, predominately TNF-α and IL-6, and the extent of adhesion formation [112,113]. A limited human pilot study has reported high concentrations of IL-6 at 12 h and IL-1 at 48 h to be associated with adhesion reformation [114].
IL-1 has been hypothesized to promote inflammation and reduce local fibrinolytic capacity, inhibiting fibrin degradation and stimulating mesothelialization of the deposited fibrin matrix [29]. Early elevations of IL-1 has been postulated to be a reliable biological marker for post-operative adhesions [115]. IL-1 has also been shown to be at a significantly high level in the peritoneum and serum of post-operative patients [116,117], suggesting a role of IL-1 in adhesions. In human mesothelial cells, IL-1β has been shown to increase the release of PAI-1, promoting a decline in local fibrinolysis [118]. Treatment with anti-IL-1 neutralizing antibodies in a rat model of peritoneal adhesion formation served to reduce adhesion formation in comparison to controls [119]. Both IL-1 and IL-6 have been shown to stimulate mesothelial and inflammatory cells to produce and release PAI-1 and 2 in order to suppress plasminogen activation [120], suggesting a role in reduction of fibrinolytic capacity.
IL-6 is considered a marker for early tissue damage [121], and is induced by IL-1 and TNF-α in mesothelial cells in a time- and dose-dependent manner [122]. The common identification of elevated IL-6 in intra-abdominal adhesions in both patients and animal models [112,114,123] indicates the important role of lymphocyte balance in regulating ongoing inflammatory and regenerative processes that are involved in adhesion formation. Activated mesothelial cells, which can be induced by inflammation, are known to produce and secrete large amounts of IL-6 in the peritoneal cavity [124]. Previous studies have also demonstrated IL-6 to be a promoter of fibrosis via altering MMP and TIMP expression [29]. Anti-IL-6 receptor monoclonal antibody treatment in a mouse model of abdominal adhesions resulted in decreased neutrophil recruitment and adhesion formation [91].
IL-8 is secreted by mesothelial cells [125] and is a potent and highly selective chemo-attractant for neutrophils [126], but more studies are needed to elucidate its role in adhesion in formation. IL-10 is a major anti-inflammatory and immunosuppressive cytokine that modulates macrophage and lymphocyte responses to pro-inflammatory stimuli [127]. IL-10 can inhibit the secretion of pro-inflammatory mediators, such as IL-1, IL-6, IL-8, IFN-γ, and TNF-α [128]. Fibroblasts isolated from adhesions demonstrate significant increases in IL-10 in comparison to peritoneal fibroblasts [129]. In murine models of post-operative abdominal adhesions, intraperitoneal injections of exogenous IL-10 has been shown to reduce formation of adhesions [130]. However, anti-IL-10 monoclonal antibody treatment had no effect on post-operative intraperitoneal adhesion formation, nor did intraperitoneal IL-10 levels change following operation in the same murine model [131]. These findings indicate that the role of IL-10 in adhesion formation has yet to be established.
Recently, IL-17 and interferon-gamma (IFN-γ) were found in peak levels 6–12 h after abdominal surgery. Pre-stimulation of IL-17 promoted PAI-1 and inhibited tPA production, while IFN-γ enhanced this effect [132]. IFN-γ has been shown to be increased post-operatively in peritoneal fluid of mice, peaking on the fourth day [133]. In a mouse model, adhesion development was shown to depend on IFN-γ, particularly derived from natural killer T-cells [134]. IFN-γ has also been shown to induce the IL-22 receptor in vitro [134]; IL-22 expression has recently been identified to rapidly increase in the abdominal cavity 12 hours after surgery [134]. As a potential stimulatory factor, some studies have shown that tumor necrosis factor-alpha (TNF-a) has been found in abundance in post-surgical peritoneal fluid and resulting in increased production of interleukins [113,119,135].

3.3.2. Transforming Growth Factor-Beta

Transforming growth factor-beta (TGF-β) is a highly studied cytokine in the context of adhesion pathophysiology. TGF-β is known to play many roles in modulating cellular behavior and the cellular environment: it is chemotactic for neutrophils, T-cells, monocytes, and fibroblasts; it induces the ECM production of various proteins, such as fibronectin, GAGs, and collagens; and it inhibits matrix degradation by altering the ratio of proteases to protease inhibitors [136]. TGF-β is hypothesized to be a principal profibrotic mediator of adhesion development. It has been shown to be co-released and work in parallel with chymase [107], as well as form local alterations of MMPs and TIMPs [38]. Mesothelial cells and adhesion fibroblasts are major sites of TGF-β expression [37], and elevated levels of TGF-β have been observed in adhesion tissues [137,138,139], in the peritoneal fluid of patients with adhesions [138,139], as well as in surgically induced adhesions in animal models [140,141]. Animal studies have shown that administration of TGF-β to the post-operative abdomen enhances formation of adhesions [77], while a blockade of TGF-β1 via inhibitory antibody treatment markedly reduces the incidence of adhesion formation [60]. An oral TGF-β type I receptor kinase inhibitor (EW-7197) has been reported to reduce incidence, quality, and tenacity of peritoneal adhesions in a dose-dependent manner via inhibition of TGF-β/Smad2/3 signaling and MMT [142]. A more recent and detailed study has reported that some of the protective anti-adhesive mechanisms of EW-7197 include a down-regulation of pro-inflammatory cytokines, attenuation of pro-inflammatory cell infiltration, inhibition of oxidative stress, decrease in excessive collagen deposition, and suppression of profibrotic genes at the site of surgery [143]. TGF-β levels post-abdominal surgery has been shown to peak at 2 h and again between 72–96 h. This correlates with the finding that TGF-β directly stimulates fibroblasts [132]. Based on these observations, it is highly likely that TGF-β is involved in adhesion maturation in later stages post-insult.

3.3.3. Vascular Endothelial Growth Factor A

Angiogenesis has been hypothesized to have a critical role in adhesion formation, although the mechanisms are not clearly understood. Vascular endothelial growth factor A (VEGF-A) is a potent member of the angiogenic factor family, and involved in coagulation, fibrinolysis, and angiogenesis [144,145]. In this context, VEGF has been reported to play a pivotal role in adhesion formation as it increases vascular permeability and promotes the deposition of the fibrin-rich matrix required for subsequent cell migration and proliferation [146]. This may ultimately lead to post-operative VEGF surges [147].
VEGF has been suggested as a key mediator in adhesion formation due to the presence of VEGF in endothelial cells of blood vessels supplying pelvic adhesions [148]. Studies also suggest a role for VEGF in adhesion formation as anti-VEGF antibody administration showed a marked reduction in adhesion formation in an open surgery murine model [149,150]. Bevacizumab, a recombinant humanized anti-VEGF antibody, has been shown to reduce pericardial adhesions through selectively exerting effects on CD-31 expression with no difference in inflammatory response, ultimately preventing leukocyte emigration and angiogenesis [151].

3.3.4. Matrix Metalloproteinases (MMPs)

Matrix metalloproteinases (MMPs) are constituents of the ECM involved in matrix activation and remodeling, cellular activation, and debridement of devitalized tissues. Several studies have demonstrated post-operative shifts in the ratios of various MMPs to their antagonists, the tissue inhibitors of matrix metalloproteinases (TIMPs) [152,153,154]. Serum MMP-9 and MMP-2 have been proposed as prognostic markers to identify post-operative adhesion formation [155]. Interestingly, gene therapy introducing catalytically inactive mutant MMP-9 via intraperitoneal instillation demonstrated a reduction in severity of post-operative peritoneal adhesions in a rat model [156]. Treatment of rat model of abdominal adhesions with berberine resulted in the prevention of primary adhesion formation via activation of MMP-3 and MMP-8 by directly blocking TIMP-1 activation core [157]. Alternations in MMP/TIMP ratios in the immediate post-operative period represent a decrease in enzymatic activity, where a chronic suppression leads to adhesions [153,154,158]. The change in ratios also suggests that proteolytic effects of MMPs, including degradation of matrix components, activation of growth factors, or the modulation of cellular migration and activity is important in adhesion prevention.

3.3.5. Substance P and Serotonin

Other components and mechanisms have also been postulated to contribute to post-surgical adhesion formation. The pro-inflammatory neuropeptide substance P that binds to the neurokinin 1 receptor (NK-1R) has been suggested to promote peritoneal adhesion formation by limiting fibrinolytic activity in the post-operative peritoneum [159,160,161,162]. Peripheral serotonin has also been reported to modulate post-operative abdominal adhesion formation by regulating oxidative stress, fibrinolytic system, angiopoiesis, and TGF-β1 expression [163].

3.4. Hypoxia and Genetic Biomarkers

As noted above, hypoxia is central to adhesion development, as it triggers a cascade of intracellular responses involving hypoxia-inducible factors, lactate, ROS, reactive nitrogen species, and insulin-like growth factors [164]. The acute production of superoxide due to tissue hypoxia can induce fibroblasts to produce profibrotic factors such as TGF-β and type I collagen that promote adhesion formation [165]. Hypoxia has been reported to decrease apoptotic indexes and increase proliferation in adhesion fibroblasts, while inducing apoptosis in normal peritoneal fibroblasts [145]. Tissue hypoxia contributes to increased oxidative stress, leading to the generation of free radicals, precipitating DNA damage, and tissue injury [166]. Although it is still unknown which cells sense the initial insult that leads to a pathological phenotype downstream, a few studies have elucidated the gene expression changes implicated in adhesion formation [39,167,168,169,170]. Micro-array analysis has identified several hub genes, such as TNF and IL6, to be significant biomarkers in the pathogenesis of post-operative peritoneal adhesions [171]. Ongoing studies are examining the potential genetic predispositions to post-operative adhesion development [169].

4. Perspective: Clinical Translation and Future Work

As highlighted in this manuscript, post-operative adhesions place significant clinical and financial burdens on patients and healthcare systems worldwide. Although various pathways and etiologies have been implicated and suggested, we are yet to fully understand the mechanisms that drive the formation of these fibrous strands. It is highly likely that post-operative adhesions have a multifactorial pathophysiology. Given this complexity, we have not been able to safely and effectively treat or prevent post-surgical adhesions on a consistent basis. Groups have endeavored to target components of pathways that are thought to contribute to post-operative adhesions. These efforts have been hamstrung by a multitude of reasons. For example, some agents have been ineffective since they require dry and blood-less surfaces, which is difficult to guarantee during an operation. Other agents have led to serious infections that have limited their widespread clinical use. Finally, some strategies have not been universally adopted as they have not been user friendly. Failures aside, these attempts have highlighted two important concepts: first, post-operative adhesions are a major clinical issue; and second, addressing them requires a better understanding of their underlying multifactorial mechanisms.
Herein, we have summarized the latest literature on post-operative adhesion formation. We have examined the various physiologic factors and inflammatory mediators that have been identified to contribute to their formation. In doing so, we have aimed to contextualize findings to better inform future research. In our review of the literature, we have realized that most work in this area has been based on an over-simplification of post-operative adhesions. For instance, in vitro studies have mostly focused on just immune cells, or they have considered inflammatory mediators in isolation, or have heavily relied on the coagulation cascade as the single-most important contributor to adhesion formation. We posit that although each of these factors play a significant role, it is highly likely that there is cross talk between each of them. Moreover, various types of surgical-induced injury can probably elicit different associations between these and yet to be discovered factors. Since surgery is inherently invasive, it is also feasible to suggest that the disruption of an environment that keeps pro-adhesion formation markers in a homeostatic state leads to their pathologic formation. This concept should be better explored in preclinical animal studies. To date, to induce adhesions, most in vivo models have used strategies (such as buttons, for example) with limited clinical translational potential. Furthermore, it is not established whether wound healing and post-surgical adhesion formation have the same cellular and molecular origins. In all likelihood, they probably do. Therefore, more research is warranted to assess what drives one to be physiologically necessary, whereas the other becomes pathologic. Are there specific factors, or a combination of, that become dysregulated? Is post-operative adhesion formation the end product of an unchecked and overactive inflammatory response to different types of injury? If so, is it feasible to intervene upon this response at a specific time-point without compromising natural healing? Finally, if post-surgical adhesions are formed, is there an opportunity to treat them in a safe and targeted manner that does not result in the reversal of the healing process? These are just a few questions that should stimulate thought-experiments and discussions that can encourage the design of future research.
As summarized here, various mechanisms and factors have been identified to contribute to post-operative adhesion formation. In some cases, groups have been able to leverage specific components to facilitate clinical translation. For example, physical barriers that have been enriched with anti-inflammatory agents have been designed and used in the clinical setting to varying degrees of success. To further enhance clinical translation, it is important to consider the following. First, although a group of cells (such as macrophages) have been shown to play a role in post-surgical adhesion formation, these cells are not all the same. For instance, pericardial macrophages may have distinct functional effects compared to peritoneal macrophages. Similarly, cells in a given body cavity can possibly drive the presence, secretion, or replenishment of markers that are different from those in another space. Second, under physiologic conditions, cells and mediators are kept in a homeostatic state that effectively balances their pro- and anti-inflammatory properties. Preclinical studies are inherently limited as they cannot recapitulate these conditions. Third, perhaps a better understanding of wound healing processes can aid us in addressing post-operative adhesions. Fourth, large animal models of post-operative adhesions are conspicuous in their absence. To maximize clinical application, these models should be designed for specific types of operations. Equally as important, to reduce heterogeneity in their reporting, objective metrics and parameters that can be used to grade adhesions must be defined and standardized. Finally, given the reasons why many of the current approaches have failed, future work in this area must focus on developing agents and strategies that can facilitate precision and personalized medicine.

5. Conclusions

Post-surgical adhesions pose a great health and financial burden. A substantial amount of work has been dedicated to better understanding the exact mechanisms of adhesion formation in the surgical setting. Inflammation and immune mediators are known to play a central role in the development and severity of post-operative adhesions. Although our understanding of some of the underlying mechanisms driving adhesion formation has significantly improved over the past two decades, literature has yet to fully explain the pathogenesis and etiology of post-surgical adhesions. To further bridge the translational gaps more rigorous preclinical studies are needed to closely examine the interactions between immune cells and mediators and post-surgical adhesion formation. To facilitate precision and personalized medicine, future therapeutic strategies should be designed to directly target specific markers.

Author Contributions

A.F.H., responsible for conception and manuscript preparation (writing and critical revision); A.N.Z. and K.J. responsible for writing sections; J.F.D., responsible for editing; P.W.M.F., responsible for supervising and approving final version. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Data Availability Statement

This Review Article presents data from peer-reviewed publications indexed in MedLine PubMed.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Diamond, M.P.; Freeman, M.L. Clinical implications of postsurgical adhesions. Hum. Reprod. Update 2001, 7, 567–576. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Liakakos, T.; Thomakos, N.; Fine, P.M.; Dervenis, C.; Young, R.L. Peritoneal adhesions: Etiology, pathophysiology, and clinical significance. Recent advances in prevention and management. Dig. Surg. 2001, 18, 260–273. [Google Scholar] [CrossRef]
  3. Goel, G.; King, T.; Daveson, A.J.; Andrews, J.M.; Krishnarajah, J.; Krause, R.; Brown, G.J.E.; Fogel, R.; Barish, C.F.; Epstein, R. Epitope-specific immunotherapy targeting CD4-positive T cells in coeliac disease: Two randomised, double-blind, placebo-controlled phase 1 studies. Lancet Gastroenterol. Hepatol. 2017, 2, 479–493. [Google Scholar] [CrossRef]
  4. Herrick, S.E.; Mutsaers, S.E.; Ozua, P.; Sulaiman, H.; Omer, A.; Boulos, P.; Foster, M.L.; Laurent, G.J. Human peritoneal adhesions are highly cellular, innervated, and vascularized. J. Pathol. 2000, 192, 67–72. [Google Scholar] [CrossRef]
  5. Lauder, C.I.; Garcea, G.; Strickland, A.; Maddern, G.J. Abdominal adhesion prevention: Still a sticky subject? Digestive Surg. 2010, 27, 347–358. [Google Scholar] [CrossRef]
  6. Parker, M.C.; Wilson, M.S.; Menzies, D.; Sunderland, G.; Thompson, J.N.; Clark, D.N.; Knigh, A.D.; Crowe, A.D. Colorectal surgery: The risk and burden of adhesion-related complications. Off. J. Assoc. Coloproctol. Great Br. Irel. 2004, 6, 506–511. [Google Scholar] [CrossRef]
  7. Ellis, H.; Moran, B.J.; Thompson, J.N.; Parker, M.C.; Wilson, M.S.; Menzies, D.; McGuire, A.; Lower, A.M.; Hawthorn, R.J.S.; O’Brien, F. Adhesion-related hospital readmissions after abdominal and pelvic surgery: A retrospective cohort study. Lancet 1999, 353, 1476–1480. [Google Scholar] [CrossRef]
  8. Schnuriger, B.; Barmparas, G.; Branco, B.C.; Lustenberger, T.; Inaba, K.; Demetriades, D. Prevention of postoperative peritoneal adhesions: A review of the literature. Am. J. Surg. 2011, 201, 111–121. [Google Scholar] [CrossRef]
  9. Parker, M.C.; Wilson, M.S.; Menzies, D.; Sunderland, G.; Clark, D.N.; Knight, A.D.; Crowe, A.M. The SCAR-3 study: 5-year adhesion-related readmission risk following lower abdominal surgical procedures. Off. J. Assoc. Coloproctol. Great Br. Irel. 2005, 7, 551–558. [Google Scholar] [CrossRef] [PubMed]
  10. Parker, M.C.; Ellis, H.; Moran, B.J.; Thompson, J.N.; Wilson, M.S.; Menzies, D.; McGuire, A.B.A.; Lower, A.M.; Hawthorn, R.J.S.; O’Brien, F. Postoperative adhesions: Ten-year follow-up of 12,584 patients undergoing lower abdominal surgery. Dis. Colon Rectum. 2001, 44, 822–829. [Google Scholar] [CrossRef] [PubMed]
  11. Ray, N.F.; Denton, W.G.; Thamer, M.; Henderson, S.C.; Perry, S. Abdominal adhesiolysis: Inpatient care and expenditures in the United States in 1994. J. Am. Coll. Surg. 1998, 186, 1–9. [Google Scholar] [CrossRef]
  12. Sikirica, V.; Bapat, B.; Candrilli, S.D.; Davis, K.L.; Wilson, M.; Johns, A. The inpatient burden of abdominal and gynecological adhesiolysis in the US. BMC Surg. 2011, 11, 13. [Google Scholar] [CrossRef] [Green Version]
  13. Weibel, M.A.; Majno, G. Peritoneal adhesions and their relation to abdominal surgery: A postmortem study. Am. J. Surg. 1973, 126, 345–353. [Google Scholar] [CrossRef]
  14. Menzies, D.; Ellis, H. Intestinal obstruction from adhesions--how big is the problem? Ann. R. Coll. Surg. Engl. 1990, 72, 60–63. [Google Scholar]
  15. Ellis, H. The clinical significance of adhesions: Focus on intestinal obstruction. Eur. J. Surg. Suppl. 1997, 5–9. [Google Scholar]
  16. Coleman, M.G.; McLain, A.D.; Moran, B.J. Impact of previous surgery on time taken for incision and division of adhesions during laparotomy. Dis. Colon Rectum. 2000, 43, 1297–1299. [Google Scholar] [CrossRef] [PubMed]
  17. Ten Broek, R.P.; Issa, Y.; van Santbrink, E.J.; Bouvy, N.D.; Kruitwagen, R.F.; Jeekel, J.; Bakkum, E.A.; Rovers, M.M. Burden of adhesions in abdominal and pelvic surgery: Systematic review and met-analysis. BMJ 2013, 347, f5588. [Google Scholar] [CrossRef] [Green Version]
  18. Lower, A.M.; Hawthorn, R.J.S.; Emeritus, H.E.; O’Brien, F.; Buchan, S.; Crowe, A.M. The impact of adhesions on hospital readmissions over ten years after 8849 open gynaecological operations: An assessment from the Surgical and Clinical Adhesions Research Study. BJOG Int. J. Obstet. Gynaecol. 2000, 107, 855–862. [Google Scholar] [CrossRef]
  19. Shahian, D.M.; O’Brien, S.M.; Filardo, G.; Ferraris, V.A.; Haan, C.K.; Rich, J.B.; Normand, S.-L.T.; DeLong, E.R.; Shewan, C.M.; Dokholyan, R.S. The Society of Thoracic Surgeons 2008 cardiac surgery risk models: Part 1—coronary artery bypass grafting surgery. Ann. Thorac Surg. 2009, 88 (Suppl. 1), S2–S22. [Google Scholar] [CrossRef]
  20. O’Brien, S.M.; Shahian, D.M.; Filardo, G.; Ferraris, V.A.; Haan, C.K.; Rich, J.B.; Normand, S.-L.T.; DeLong, E.R.; Shewan, C.M.; Dokholyan, R.S. The Society of Thoracic Surgeons 2008 cardiac surgery risk models: Part 2—isolated valve surgery. Ann. Thorac. Surg. 2009, 88 (Suppl. 1), S23–S42. [Google Scholar] [CrossRef] [PubMed]
  21. Jacobs, J.P.; Mavroudis, C.; Quintessenza, J.A.; Chai, P.J.; Pasquali, S.K.; Hill, K.D.; Vricella, L.A.; Jacobs, M.L.; Dearani, J.A.; Cameron, D. Reoperations for pediatric and congenital heart disease: An analysis of the Society of Thoracic Surgeons (STS) congenital heart surgery database. Semin Thorac. Cardiovasc Surg. Pediatr. Card. Surg. Annu. 2014, 17, 2–8. [Google Scholar] [CrossRef] [Green Version]
  22. Cannata, A.; Petrella, D.; Russo, C.F.; Bruschi, G.; Fratto, P.; Gambacorta, M.; Martinelli, L. Postsurgical intrapericardial adhesions: Mechanisms of formation and prevention. Ann. Thorac. Surg. 2013, 95, 1818–1826. [Google Scholar] [CrossRef]
  23. Nkere, U.U. Postoperative adhesion formation and the use of adhesion preventing techniques in cardiac and general surgery. Am. Soc. Artif. Intern. Organs 2000, 46, 654–656. [Google Scholar] [CrossRef]
  24. Nkere, U.U.; Whawell, S.A.; Sarraf, C.E.; Schofield, J.B.; Thompson, J.N.; Taylor, K.M. Pericardial trauma and adhesions in relation to reoperative cardiac surgery. Thorac. Cardiovasc. Surg. 1995, 43, 338–346. [Google Scholar] [CrossRef]
  25. Coccolini, F.; Ansaloni, L.; Manfredi, R.; Campanati, L.; Poiasina, E.; Bertoli, P.; Capponi, M.G.; Sartelli, M.; Di Saverio, S.; Cucchi, M. Peritoneal adhesion index (PAI): Proposal of a score for the "ignored iceberg" of medicine and surgery. World J. Emerg Surg. 2013, 8, 6. [Google Scholar] [CrossRef] [Green Version]
  26. Milligan, D.W.; Raftery, A.T. Observations on the pathogenesis of peritoneal adhesions: A light and electron microscopical study. Br. J. Surg. 1974, 61, 274–280. [Google Scholar] [CrossRef] [PubMed]
  27. Binda, M.M.; Molinas, C.R.; Koninckx, P.R. Reactive oxygen species and adhesion formation: Clinical implications in adhesion prevention. Hum. Reproduction. 2003, 18, 2503–2507. [Google Scholar] [CrossRef] [Green Version]
  28. Holmdahl, L.; Eriksson, E.; al-Jabreen, M.; Risberg, B. Fibrinolysis in human peritoneum during operation. Surgery 1996, 119, 701–705. [Google Scholar] [CrossRef]
  29. Holmdahl, L.; Ivarsson, M.L. The role of cytokines, coagulation, and fibrinolysis in peritoneal tissue repair. Eur. J. Surg. 1999, 165, 1012–1019. [Google Scholar] [PubMed]
  30. Sun, Z.; Sessler, D.I.; Dalton, J.E.; Devereaux, P.J.; Shahinyan, A.; Naylor, A.J.; Hutcherson, M.T.; Finnegan, P.S.; Tandon, V.; Darvish-Kazem, S. Postoperative Hypoxemia Is Common and Persistent: A Prospective Blinded Observational Study. Anesth. Analg. 2015, 121, 709–715. [Google Scholar] [CrossRef] [Green Version]
  31. Risberg, B.; Stenberg, B. Modulation of tissue fibrinolysis from hypoxia and hyperoxia. Thromb Res. 1985, 38, 129–136. [Google Scholar] [CrossRef]
  32. Yan, S.-F.; Mackman, N.; Kisiel, W.; Stern, D.M.; Pinsky, D.J. Hypoxia/Hypoxemia-Induced Activation of the Procoagulant Pathways and the Pathogenesis of Ischemia-Associated Thrombosis. Arterioscler. Thromb. Vasc. Biol. 1999, 19, 2029–2035. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Gertler, J.P.; Perry, L.; L’Italien, G.; Chung-Welch, N.; Cambria, R.P.; Orkin, R.; Abbot, W.M. Ambient oxygen tension modulates endothelial fibrinolysis. J. Vasc. Surg. 1993, 18, 939–945. [Google Scholar] [CrossRef] [Green Version]
  34. Palta, S.; Saroa, R.; Palta, A. Overview of the coagulation system. Indian J. Anaesth. 2014, 58, 515–523. [Google Scholar] [CrossRef] [PubMed]
  35. DiZerega, G.S. Biochemical events in peritoneal tissue repair. Eur. J. Surg. Supplement. Acta Chir. Suppl. 1997, 10–16. [Google Scholar]
  36. Di Filippo, C.; Falsetto, A.; de Pascale, V.; Tufariello, E.; de Lucia, D.; Rossi, F.; D’amico, M.; Cenamo, A. Plasma levels of t-PA and PAI-1 correlate with the formation of experimental post-surgical peritoneal adhesions. Mediat. Inflamm. 2006, 2006, 13901. [Google Scholar] [CrossRef] [PubMed]
  37. Chegini, N. Peritoneal molecular environment, adhesion formation and clinical implication. Front. Biosci. 2002, 7, e91–e115. [Google Scholar]
  38. Chegini, N. TGF-beta system: The principal profibrotic mediator of peritoneal adhesion formation. Semin. Reprod. Med. 2008, 26, 298–312. [Google Scholar] [CrossRef]
  39. Fortin, C.N.; Saed, G.M.; Diamond, M.P. Predisposing factors to post-operative adhesion development. Hum. Reprod. Update. 2015, 21, 536–551. [Google Scholar] [CrossRef] [Green Version]
  40. Mutsaers, S.E.; Birnie, K.; Lansley, S.; Herrick, S.E.; Lim, C.-B.; Prêle, C.M. Mesothelial cells in tissue repair and fibrosis. Front. Pharmacol. 2015, 6, 113. [Google Scholar] [CrossRef] [Green Version]
  41. Tsai, J.M.; Shoham, M.; Fernhoff, N.B.; George, B.M.; Marjon, K.D.; McCracken, M.N.; Kao, C.S.; Sinha, R.; Volmer, A.K.; Miyanishi, M. Neutrophil and monocyte kinetics play critical roles in mouse peritoneal adhesion formation. Blood Adv. 2019, 3, 2713–2721. [Google Scholar]
  42. Sandoval, P.; Jimenez-Heffernan, J.A.; Guerra-Azcona, G.; Perez-Lozano, M.L.; Rynne-Vidal, A.; Albar-Vizcaino, P.; Gil-Vera, F.; Martin, P.; Martin, P.; Coronado, M.J.; et al. Mesothelial-to-mesenchymal transition in the pathogenesis of post-surgical peritoneal adhesions. J. Pathol. 2016, 239, 48–59. [Google Scholar] [CrossRef] [PubMed]
  43. Jin, X.; Ren, S.; Macarak, E.; Rosenbloom, J. Pathobiological mechanisms of peritoneal adhesions: The mesenchymal transition of rat peritoneal mesothelial cells induced by TGF-β1 and IL-6 requires activation of Erk1/2 and Smad2 linker region phosphorylation. Matrix Biol. 2016, 51, 55–64. [Google Scholar] [CrossRef]
  44. Yáñez-Mó, M.; Lara-Pezzi, E.; Selgas, R.; Ramírez-Huesca, M.; Domínguez-Jiménez, C.; Jiménez-Heffernan, J.A.; Aguilera, A.; Sánchez-Tomero, J.A.; Bajo, M.A.; Álvarez, V.; et al. Peritoneal Dialysis and Epithelial-to-Mesenchymal Transition of Mesothelial Cells. N. Engl. J. Med. 2003, 348, 403–413. [Google Scholar] [CrossRef] [PubMed]
  45. Raftery, A.T. Regeneration of parietal and visceral peritoneum in the immature animal: A light and electron microscopical study. Br. J. Surg. 1973, 60, 969–975. [Google Scholar] [CrossRef] [PubMed]
  46. Menzies, D. Peritoneal adhesions. Incidence, cause, and prevention. Surg. Annu. 1992, 24 Pt 1, 27–45. [Google Scholar] [PubMed]
  47. Cheong, Y.C.; Laird, S.M.; Li, T.C.; Shelton, J.B.; Ledger, W.L.; Cooke, I.D. Peritoneal healing and adhesion formation/reformation. Hum. Reprod. Update 2001, 7, 556–566. [Google Scholar] [CrossRef] [PubMed]
  48. Jaworska-Wilczynska, M.; Trzaskoma, P.; Szczepankiewicz, A.A.; Hryniewiecki, T. Pericardium: Structure and function in health and disease. Folia Histochem. Cytobiol. 2016, 54, 121–125. [Google Scholar] [CrossRef] [Green Version]
  49. Schade, D.S.; Williamson, J.R. The pathogenesis of peritoneal adhesions: An ultrastructural study. Ann. Surg. 1968, 167, 500–510. [Google Scholar] [CrossRef] [PubMed]
  50. DiZerega, G.S.; Campeau, J.D. Peritoneal repair and post-surgical adhesion formation. Hum. Reprod. Update. 2001, 7, 547–555. [Google Scholar] [CrossRef] [PubMed]
  51. Suzuki, T.; Kono, T.; Bochimoto, H.; Hira, Y.; Watanabe, T.; Furukawa, H. An injured tissue affects the opposite intact peritoneum during postoperative adhesion formation. Sci. Rep. 2015, 5, 7668. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  52. Inagaki, N.F.; Inagaki, F.F.; Kokudo, N.; Miyajima, A. Use of mouse liver mesothelial cells to prevent postoperative adhesion and promote liver regeneration after hepatectomy. J. Hepatol. 2015, 62, 1141–1147. [Google Scholar] [CrossRef] [Green Version]
  53. Betjes, M.G.; Tuk, C.W.; Struijk, D.G.; Krediet, R.T.; Arisz, L.; Beelen, R.H. Adherence of Staphylococci to plastic, mesothelial cells and mesothelial extracellular matrix. Adv. Perit. Dial. 1992, 8, 215–218. [Google Scholar] [PubMed]
  54. Tsai, J.M.; Sinha, R.; Seita, J.; Fernhoff, N.; Christ, S.; Koopmans, T.; Krampitz, G.W.; McKenna, K.M.; Xing, L.; Sandholzer, M.; et al. Surgical adhesions in mice are derived from mesothelial cells and can be targeted by antibodies against mesothelial markers. Sci. Transl. Med. 2018, 10. [Google Scholar] [CrossRef] [Green Version]
  55. Fischer, A.; Koopmans, T.; Ramesh, P.; Christ, S.; Strunz, M.; Wannemacher, J.; Aichler, M.; Feuchtinger, A.; Walch, A.; Ansari, M.; et al. Post-surgical adhesions are triggered by calcium-dependent membrane bridges between mesothelial surfaces. Nat. Commun. 2020, 11, 3068. [Google Scholar] [CrossRef]
  56. Boland, G.M.; Weigel, R.J. Formation and Prevention of Postoperative Abdominal Adhesions. J. Surg. Res. 2006, 132, 3–12. [Google Scholar] [CrossRef]
  57. Ellis, H.; Harrison, W.; Hugh, T.B. The healing of the peritneum under normal and pathological conditions. Br. J. Surg. 1965, 524, 71–76. [Google Scholar]
  58. Raftery, A.T. Regeneration of parietal and visceral peritoneum: An electron microscopical study. J. Anat. 1973, 115 Pt 3, 375–392. [Google Scholar]
  59. Hellebrekers, B.W.; Kooistra, T. Pathogenesis of postoperative adhesion formation. Br. J. Surg. 2011, 98, 1503–1516. [Google Scholar] [CrossRef]
  60. Lucas, P.A.; Warejcka, D.J.; Young, H.E.; Lee, B.Y. Formation of Abdominal Adhesions Is Inhibited by Antibodies to Transforming Growth Factor-β1. J. Surg. Res. 1996, 65, 135–138. [Google Scholar] [CrossRef] [PubMed]
  61. Foster, D.S.; Marshall, C.D.; Gulati, G.S.; Chinta, M.S.; Nguyen, A.; Salhotra, A.; Jines, R.E.; Burcham, A.; Lerbs, T.; Cui, L. Elucidating the fundamental fibrotic processes driving abdominal adhesion formation. Nat. Commun. 2020, 11, 4061. [Google Scholar] [CrossRef]
  62. Buckman, R.F.; Woods, M.; Sargent, L.; Gervin, A.S. A unifying pathogenetic mechanism in the etiology of intraperitoneal adhesions. J. Surg. Res. 1976, 20, 1–5. [Google Scholar] [CrossRef]
  63. Holmadhl, L.; al-Jabreen, M.; Xia, G.; Risberg, B. The impact of starch-powdered gloves on the formation of adhesions in rats. Acta Chirurgica. 1994, 160, 257–261. [Google Scholar]
  64. Belluco, C.; Meggiolaro, F.; Pressato, D.; Pavesio, A.; Bigon, E.; Donà, M.; Forlin, M.; Nitti, D.; Lise, M. Prevention of postsurgical adhesions with an autocrosslinked hyaluronan derivative gel. J. Surg. Res. 2001, 100, 217–221. [Google Scholar] [CrossRef] [PubMed]
  65. Xu, X.; Rivkind, A.; Pappo, O.; Pikarsky, A.; Levi-Schaffer, F. Role of mast cells and myofibroblasts in human peritoneal adhesion formation. Ann. Surg. 2002, 236, 593–601. [Google Scholar] [CrossRef]
  66. Hinz, B.; Phan, S.H.; Thannickal, V.J.; Galli, A.; Bochaton-Piallat, M.-L.; Gabbiani, G. The Myofibroblast: One Function, Multiple Origins. Am. J. Pathol. 2007, 170, 1807–1816. [Google Scholar] [CrossRef]
  67. Wei, G.; Chen, X.; Wang, G.; Jia, P.; Xu, Q.; Ping, G.; Wang, K.; Li, X. Inhibition of cyclooxygenase-2 prevents intra-abdominal adhesions by decreasing activity of peritoneal fibroblasts. Drug Des. Devel. Ther. 2015, 9, 3083–3098. [Google Scholar]
  68. Rout, U.K.; Saed, G.M.; Diamond, M.P. Expression pattern and regulation of genes differ between fibroblasts of adhesion and normal human peritoneum. Reprod. Biol. Endocrinol. 2005, 3, 1. [Google Scholar] [CrossRef] [Green Version]
  69. Saed, G.M.; Diamond, M.P. Hypoxia-induced irreversible up-regulation of type I collagen and transforming growth factor-β1 in human peritoneal fibroblasts. Fertil. Steril. 2002, 78, 144–147. [Google Scholar] [CrossRef]
  70. Saed, G.M.; Munkarah, A.R.; Diamond, M.P. Cyclooxygenase-2 is expressed in human fibroblasts isolated from intraperitoneal adhesions but not from normal peritoneal tissues. Fertil Steril. 2003, 79, 1404–1408. [Google Scholar] [CrossRef]
  71. Saed, G.M.; Zhang, W.; Chegini, N.; Holmdahl, L.; Diamond, M.P. Transforming growth factor beta isoforms production by human peritoneal mesothelial cells after exposure to hypoxia. Am. J. Reprod. Immunol. 2000, 43, 285–291. [Google Scholar] [CrossRef] [PubMed]
  72. Saed, G.M.; Munkarah, A.R.; Abu-Soud, H.M.; Diamond, M.P. Hypoxia upregulates cyclooxygenase-2 and prostaglandin E2 levels in human peritoneal fibroblasts. Fertil. Steril. 2005, 83, 1216–1219. [Google Scholar] [CrossRef]
  73. Jiang, Z.L.; Zhu, X.; Diamond, M.P.; Abu-Soud, H.M.; Saed, G.M. Nitric oxide synthase isoforms expression in fibroblasts isolated from human normal peritoneum and adhesion tissues. Fertil. Steril. 2008, 90, 769–774. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  74. Saed, G.M.; Diamond, M.P. Differential expression of alpha smooth muscle cell actin in human fibroblasts isolated from intraperitoneal adhesions and normal peritoneal tissues. Fertil. Steril. 2004, 82 (Suppl. 3), 1188–1192. [Google Scholar] [CrossRef]
  75. Chen, Y.T.; Chang, Y.T.; Pan, S.Y.; Chou, Y.H.; Chang, F.C.; Yeh, P.Y.; Liu, Y.H.; Chiang, W.C.; Chen, Y.M.; Wu, K.D.; et al. Lineage tracing reveals distinctive fates for mesothelial cells and submesothelial fibroblasts during peritoneal injury. J. Am. Soc. Nephrol. 2014, 25, 2847–2858. [Google Scholar] [CrossRef] [Green Version]
  76. Park, D.S.J.; Regmi, S.C.; Svystonyuk, D.A.; Teng, G.; Belke, D.; Turnbull, J.; Guzzardi, D.G.; Kang, S.; Cowman, M.K.; Schmidt, T.A.; et al. Human pericardial proteoglycan 4 (lubricin): Implications for postcardiotomy intrathoracic adhesion formation. J. Thorac. Cardiovasc. Surg. 2018, 156, 1598–1608.e1. [Google Scholar] [CrossRef] [PubMed]
  77. Williams, R.S.; Rossi, A.M.; Chegini, N.; Schultz, G. Effect of transforming growth factor β on postoperative adhesion formation and intact peritoneum. J. Surg. Res. 1992, 52, 65–70. [Google Scholar] [CrossRef]
  78. Haney, A.F. Identification of macrophages at the site of peritoneal injury: Evidence supporting a direct role for peritoneal macrophages in healing injured peritoneum. Fertil. Steril. 2000, 73, 988–995. [Google Scholar] [CrossRef]
  79. Binnebösel, M.; Rosch, R.; Junge, K.; Lynen-Jansen, P.; Schumpelick, V.; Klinge, U. Macrophage and T-lymphocyte Infiltrates in Human Peritoneal Adhesions Indicate a Chronic Inflammatory Disease. World J. Surg. 2008, 32, 296–304. [Google Scholar] [CrossRef]
  80. Turza, K.C.; Butler, C.E. Adhesions and meshes: Synthetic versus bioprosthetic. Plast. Reconstr. Surg. 2012, 130 (Suppl. 2), 206s–213s. [Google Scholar] [CrossRef]
  81. Ergul, E.; Korukluoglu, B. Peritoneal adhesions: Facing the enemy. Int. J. Surg. 2008, 6, 253–260. [Google Scholar] [CrossRef] [Green Version]
  82. Canturk, N.Z.; Vural, B.; Esen, N.; Canturk, Z.; Oktay, G.; Kirkali, G.; Solakoglu, S. Effects of granulocyte-macrophage colony-stimulating factor on incisional wound healing in an experimental diabetic rat model. Endocr. Res. 1999, 25, 105–116. [Google Scholar] [CrossRef]
  83. Honjo, K.; Munakata, S.; Tashiro, Y.; Salama, Y.; Shimazu, H.; Eiamboonsert, S.; Dhahri, D.; Ichimura, A.; Dan, T.; Miyata, T.; et al. Plasminogen activator inhibitor-1 regulates macrophage-dependent postoperative adhesion by enhancing EGF-HER1 signaling in mice. FASEB J. 2017, 31, 2625–2637. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  84. Ar’Rajab, A.; Dawidson, I.; Sentementes, J.; Sikes, P.; Harris, R.; Mileski, W. Enhancement of Peritoneal Macrophages Reduces Postoperative Peritoneal Adhesion Formation. J. Surg. Res. 1995, 58, 307–312. [Google Scholar] [CrossRef] [PubMed]
  85. Hoshino, A.; Kawamura, Y.I.; Yasuhara, M.; Toyama-Sorimachi, N.; Yamamoto, K.; Matsukawa, A.; Lira, S.A.; Dohi, T. Inhibition of CCL1-CCR8 Interaction Prevents Aggregation of Macrophages and Development of Peritoneal Adhesions. J. Immunol. 2007, 178, 5296–5304. [Google Scholar] [CrossRef]
  86. Sindrilaru, A.; Scharffetter-Kochanek, K. Disclosure of the Culprits: Macrophages-Versatile Regulators of Wound Healing. Adv. Wound Care 2013, 2, 357–368. [Google Scholar] [CrossRef] [Green Version]
  87. Orecchioni, M.; Ghosheh, Y.; Pramod, A.B.; Ley, K. Macrophage Polarization: Different Gene Signatures in M1(LPS+) vs. Classically and M2(LPS–) vs. Alternatively Activated Macrophages. Front. Immunol. 2019, 10, 1084. [Google Scholar] [CrossRef] [PubMed]
  88. Martinez, F.O.; Gordon, S. The M1 and M2 paradigm of macrophage activation: Time for reassessment. F1000Prime Rep. 2014, 6, 13. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  89. Hong, G.S.; Schwandt, T.; Stein, K.; Schneiker, B.; Kummer, M.P.; Heneka, M.T.; Kitamura, K.; Kallf, J.K.; Wehner, S. Effects of macrophage-dependent peroxisome proliferator-activated receptor γ signalling on adhesion formation after abdominal surgery in an experimental model. Br. J. Surg. 2015, 102, 1506–1516. [Google Scholar] [CrossRef]
  90. Rodgers, K.E.; diZerega, G.S. Modulation of peritoneal re-epithelialization by postsurgical macrophages. J. Surg. Research. 1992, 53, 542–548. [Google Scholar] [CrossRef]
  91. Uyama, N.; Tsutsui, H.; Wu, S.; Yasuda, K.; Hatano, E.; Qin, X.-Y.; Kojima, S.; Fujimoto, J. Anti-interleukin-6 receptor antibody treatment ameliorates postoperative adhesion formation. Sci. Reports. 2019, 9, 17558. [Google Scholar] [CrossRef] [Green Version]
  92. Ribeiro, R.A.; Flores, C.A.; Cunha, F.Q.; Ferreira, S.H. IL-8 causes in vivo neutrophil migration by a cell-dependent mechanism. Immunology 1991, 73, 472–477. [Google Scholar]
  93. Vural, B.; Cantürk, N.Z.; Esen, N.; Solakoglu, S.; Cantürk, Z.; Kirkali, G.; Sökmensüer, C. The role of neutrophils in the formation of peritoneal adhesions. Hum. Reprod. 1999, 14, 49–54. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  94. Ten Raa, S.; van den Tol, M.P.; Sluiter, W.; Hofland, L.J.; van Eijck, C.H.; Jeekel, H. The role of neutrophils and oxygen free radicals in post-operative adhesions. J. Surg. Res. 2006, 136, 45–52. [Google Scholar] [CrossRef] [PubMed]
  95. Arfors, K.E.; Lundberg, C.; Lindbom, L.; Lundberg, K.; Beatty, P.G.; Harlan, J.M. A monoclonal antibody to the membrane glycoprotein complex CD18 inhibits polymorphonuclear leukocyte accumulation and plasma leakage in vivo. Blood 1987, 69, 338–340. [Google Scholar] [CrossRef] [PubMed]
  96. Ar’Rajab, A.; Mileski, W.; Sentementes, J.T.; Sikes, P.; Harris, R.B.; Dawidson, I.J. The role of neutrophils in peritoneal adhesion formation. J. Surg. Res. 1996, 61, 143–146. [Google Scholar] [CrossRef]
  97. Awonuga, A.O.; Belotte, J.; Abuanzeh, S.; Fletcher, N.M.; Diamond, M.P.; Saed, G.M. Advances in the Pathogenesis of Adhesion Development: The Role of Oxidative Stress. Reprod. Sci. 2014, 21, 823–836. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  98. Roy, S.; Clark, C.J.; Mohebali, K.; Bhatt, U.; Wallace, W.A.; Nahman, N.S.; Ellison, E.C.; Melvin, W.S.; Sen, C.K. Reactive oxygen species and EGR-1 gene expression in surgical postoperative peritoneal adhesions. World J. Surg. 2004, 28, 316–320. [Google Scholar]
  99. Binnebösel, M.; Klink, C.D.; Serno, J.; Jansen, P.L.; von Trotha, K.T.; Neumann, U.P.; Junge, K. Chronological evaluation of inflammatory mediators during peritoneal adhesion formation using a rat model. Langenbeck’s Arch. Surg. 2011, 396, 371–378. [Google Scholar] [CrossRef]
  100. Chung, D.R.; Chitnis, T.; Panzo, R.J.; Kasper, D.L.; Sayegh, M.H.; Tzianabos, A.O. CD4+ T cells regulate surgical and postinfectious adhesion formation. J. Exp. Medicine. 2002, 195, 1471–1478. [Google Scholar] [CrossRef] [Green Version]
  101. Tzianabos, A.O.; Holsti, M.A.; Zheng, X.X.; Stucchi, A.F.; Kuchroo, V.K.; Strom, T.B.; Glimcher, L.H.; Cruikshank, W.W. Functional Th1 cells are required for surgical adhesion formation in a murine model. J. Immunol. 2008, 180, 6970–6976. [Google Scholar] [CrossRef] [Green Version]
  102. Ozbilgin, K.; Üner, M.A.; Ozkut, M.; Hasdemir, P.S. The effects of pirfenidone on T helper cells in prevention of intraperitoneal adhesions. Kaohsiung J. Med. Sciences. 2017, 33, 271–276. [Google Scholar] [CrossRef] [Green Version]
  103. McLoughlin, R.M.; Jenkins, B.J.; Grail, D.; Williams, A.S.; Fielding, C.A.; Parker, C.R.; Ernst, M.; Topley, N.; Jones, S.A. IL-6 trans-signaling via STAT3 directs T cell infiltration in acute inflammation. Proc. Natl. Acad. Sci. USA 2005, 102, 9589–9594. [Google Scholar] [CrossRef] [Green Version]
  104. Maciver, A.H.; McCall, M.; James Shapiro, A.M. Intra-abdominal adhesions: Cellular mechanisms and strategies for prevention. Int. J. Surgery. 2011, 9, 589–594. [Google Scholar] [CrossRef] [Green Version]
  105. Canturk, N.Z.; Vural, B.; Cubukcu, A.; Duzcen, E.; Utkan, Z.; Dulger, M. Experimental study on the role of mast cells in peritoneal adhesion formation. East. Afr. Med. J. 1999, 76, 233–236. [Google Scholar]
  106. Yao, Y.-L.; Ishihara, T.; Takai, S.; Miyazaki, M.; Mita, S. Association between the Expression of Mast Cell Chymase and Intraperitoneal Adhesion Formation in Mice. J. Surg. Res. 2000, 92, 40–44. [Google Scholar] [CrossRef] [PubMed]
  107. Soga, Y.; Takai, S.; Koyama, T.; Okamoto, Y.; Ikeda, T.; Nishimura, K.; Miyazaki, M.; Komeda, M. Attenuation of adhesion formation after cardiac surgery with a chymase inhibitor in a hamster model. J. Thorac. Cardiovasc. Surg. 2004, 127, 72–78. [Google Scholar] [CrossRef] [Green Version]
  108. Cahill, R.A.; Wang, J.H.; Soohkai, S.; Redmond, H.P. Mast cells facilitate local VEGF release as an early event in the pathogenesis of postoperative peritoneal adhesions. Surgery 2006, 140, 108–112. [Google Scholar] [CrossRef] [PubMed]
  109. Arjmand, M.H. The association between visceral adiposity with systemic inflammation, oxidative stress, and risk of post-surgical adhesion. Arch. Physiol. Biochem. 2020, 1–6. [Google Scholar] [CrossRef]
  110. Pismensky, S.V.; Kalzhanov, Z.R.; Eliseeva, M.Y.; Kosmas, I.P.; Mynbaev, O.A. Severe inflammatory reaction induced by peritoneal trauma is the key driving mechanism of postoperative adhesion formation. BMC Surg. 2011, 11, 30. [Google Scholar] [CrossRef] [Green Version]
  111. Reber, P.U.; Andrén, S.; Schmied, B.; Büchler, M.W. Cytokines in surgical trauma: Cholecystectomy as an example. Dig. Surg. 1998, 15, 92–101. [Google Scholar] [CrossRef] [PubMed]
  112. Buyalos, R.P.; Funari, V.A.; Azziz, R.; Watson, J.M.; Martinez-Maza, O. Elevated interleukin-6 levels in peritoneal fluid of patients with pelvic pathology. Fertil. Steril. 1992, 58, 302–306. [Google Scholar] [CrossRef]
  113. Kaidi, A.A.; Gurchumelidze, T.; Nazzal, M.; Figert, P.; Vanterpool, C.; Silva, Y. Tumor necrosis factor-alpha: A marker for peritoneal adhesion formation. J. Surg. Res. 1995, 58, 516–518. [Google Scholar] [CrossRef] [PubMed]
  114. Cheong, Y.C.; Laird, S.M.; Shelton, J.B.; Ledger, W.L.; Li, T.C.; Cooke, I.D. The correlation of adhesions and peritoneal fluid cytokine concentrations: A pilot study. Hum. Reprod. 2002, 17, 1039–1045. [Google Scholar] [CrossRef] [Green Version]
  115. Saba, A.A.; Godziachvili, V.; Mavani, A.K.; Silva, Y.J. Serum levels of interleukin 1 and tumor necrosis factor alpha correlate with peritoneal adhesion grades in humans after major abdominal surgery. Am. Surg. 1998, 64, 734–736. [Google Scholar] [PubMed]
  116. Tsukada, K.; Katoh, H.; Suzuki, T.; Takenoshita, S.; Nagamachi, Y. Correlations of peritoneal interleukin-6, serum beta-2 microglobulin and urinary beta-2 microglobulin after elective abdominal surgery. Acta Pathol. Microbiol. Et Immunol. Scand. 1993, 101, 409–412. [Google Scholar] [CrossRef] [PubMed]
  117. Yoshikawa, H.; Kawamura, I.; Fujita, M.; Tsukada, H.; Arakawa, M.; Mitsuyama, M. Membrane damage and interleukin-1 production in murine macrophages exposed to listeriolysin O. Infect. Immun. 1993, 61, 1334–1339. [Google Scholar] [CrossRef] [Green Version]
  118. Whawell, S.A.; Thompson, J.N. Cytokine-induced release of plasminogen activator inhibitor-1 by human mesothelial cells. Eur. J. Surg. 1995, 161, 315–318. [Google Scholar]
  119. Kaidi, A.A.; Nazzal, M.; Gurchumelidze, T.; Ali, M.A.; Dawe, E.J.; Silva, Y.J. Preoperative administration of antibodies against tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1) and their impact on peritoneal adhesion formation. Am. Surg. 1995, 61, 569–572. [Google Scholar]
  120. Whawell, S.A.; Wang, Y.; Fleming, K.A.; Thompson, E.M.; Thompson, J.N. Localization of plasminogen activator inhibitor-1 production in inflamed appendix by in situ mRNA hybridization. J. Pathol. 1993, 169, 67–71. [Google Scholar] [CrossRef]
  121. Shenkin, A.; Fraser, W.D.; Series, J.; Winstanley, F.P.; McCartney, A.C.; Burns, H.J.; Van Damme, J. The serum interleukin 6 response to elective surgery. Lymphokine Res. 1989, 8, 123–127. [Google Scholar]
  122. Topley, N.; Jörres, A.; Luttmann, W.; Petersen, M.M.; Lang, M.J.; Thierauch, K.H.; Müller, M.; Coles, G.A.; Davies, M.; Williams, J.D. Human peritoneal mesothelial cells synthesize interleukin-6: Induction by IL-1 beta and TNF alpha. Kidney Int. 1993, 43, 226–233. [Google Scholar] [CrossRef] [Green Version]
  123. Cheong, Y.C.; Shelton, J.B.; Laird, S.M.; Richmond, M.; Kudesia, G.; Li, T.C.; Letger, W.L. IL-1, IL-6 and TNF-α concentrations in the peritoneal fluid of women with pelvic adhesions. Hum. Reproduction. 2002, 17, 69–75. [Google Scholar] [CrossRef]
  124. Witowski, J.; Jörres, A.; Coles, G.A.; Williams, J.D.; Topley, N. Superinduction of IL-6 synthesis in human peritoneal mesothelial cells is related to the induction and stabilization of IL-6 mRNA. Kidney Int. 1996, 50, 1212–1223. [Google Scholar] [CrossRef] [Green Version]
  125. Jonjić, N.; Peri, G.; Bernasconi, S.; Sciacca, F.L.; Colotta, F.; Pelicci, P.; Lanfrancone, L.; Mantovani, A. Expression of adhesion molecules and chemotactic cytokines in cultured human mesothelial cells. J. Exp. Med. 1992, 176, 1165–1174. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  126. De Oliveira, S.; Reyes-Aldasoro, C.C.; Candel, S.; Renshaw, S.A.; Mulero, V.; Calado, A. Cxcl8 (IL-8) mediates neutrophil recruitment and behavior in the zebrafish inflammatory response. J. Immunol. 2013, 190, 4349–4359. [Google Scholar] [CrossRef] [PubMed]
  127. Ouyang, W.; Rutz, S.; Crellin, N.K.; Valdez, P.A.; Hymowitz, S.G. Regulation and functions of the IL-10 family of cytokines in inflammation and disease. Annu. Rev. Immunol. 2011, 29, 71–109. [Google Scholar] [CrossRef] [PubMed]
  128. Wang, S.; Gao, X.; Shen, G.; Wang, W.; Li, J.; Zhao, J.; Wei, Y.Q.; Edwards, C.K. Interleukin-10 deficiency impairs regulatory T cell-derived neuropilin-1 functions and promotes Th1 and Th17 immunity. Sci. Rep. 2016, 6, 24249. [Google Scholar] [CrossRef] [Green Version]
  129. Saed, G.M.; Zhang, W.; Diamond, M.P. Molecular characterization of fibroblasts isolated from human peritoneum and adhesions. Fertil. Steril. 2001, 75, 763–768. [Google Scholar] [CrossRef]
  130. Montz, F.J.; Holschneider, C.H.; Bozuk, M.; Gotlieb, W.H.; Martinez-Maza, O. Interleukin 10: Ability to minimize postoperative intraperitoneal adhesion formation in a murine model. Fertil. Steril. 1994, 61, 1136–1140. [Google Scholar] [CrossRef]
  131. Holschneider, C.H.; Cristoforoni, P.M.; Ghosh, K.; Punyasavatsut, M.; Abed, E.; Montz, F.J. Endogenous versus exogenous IL-10 in postoperative intraperitoneal adhesion formation in a murine model. J. Surg. Res. 1997, 70, 138–143. [Google Scholar] [CrossRef]
  132. Wang, G.; Wu, K.; Li, W.; Zhao, E.; Shi, L.; Wang, J.; Shuai, X.; Cai, K.; Lu, X.; Tao, K. Role of IL-17 and TGF-beta in peritoneal adhesion formation after surgical trauma. Off. Publ. Wound Heal. Soc. Eur. Tissue Repair Soc. 2014, 22, 631–639. [Google Scholar]
  133. Rong, H.; Tang, X.M.; Zhao, Y.; Juneja, S.C.; Fay, M.F.; Williams, R.S. Postsurgical intraperitoneal exposure to glove powders modulates inflammatory and immune-related cytokine production. Off. Publ. Wound Heal. Soc. Eur. Tissue Repair Soc. 1997, 5, 89–96. [Google Scholar] [CrossRef] [PubMed]
  134. Wang, Q.; Huang, Y.; Zhou, R.; Wu, K.; Li, W.; Shi, L.; Xia, Z.; Tao, K.; Wang, G.; Wang, G. Regulation and function of IL-22 in peritoneal adhesion formation after abdominal surgery. Wound Repair Regen. 2020, 28, 105–117. [Google Scholar] [CrossRef] [PubMed]
  135. Betjes, M.G.; Tuk, C.W.; Struijk, D.G.; Krediet, R.T.; Arisz, L.; Hart, M.; Beelen, R.H.J. Interleukin-8 production by human peritoneal mesothelial cells in response to tumor necrosis factor-alpha, interleukin-1, and medium conditioned by macrophages cocultured with Staphylococcus epidermidis. J. Infect. Dis. 1993, 168, 1202–1210. [Google Scholar] [CrossRef]
  136. Chegini, N. The role of growth factors in peritoneal healing: Transforming growth factor beta (TGF-beta). Eur. J. Surg. Suppl. 1997, 577, 17–23. [Google Scholar]
  137. Holmdahl, L.; Kotseos, K.; Bergström, M.; Falk, P.; Ivarsson, M.L.; Chegini, N. Overproduction of transforming growth factor-beta1 (TGF-beta1) is associated with adhesion formation and peritoneal fibrinolytic impairment. Surgery 2001, 129, 626–632. [Google Scholar] [CrossRef]
  138. Hobson, K.G.; DeWing, M.; Ho, H.S.; Wolfe, B.M.; Cho, K.; Greenhalgh, D.G. Expression of Transforming Growth Factor β1 in Patients with and Without Previous Abdominal Surgery. Arch. Surg. 2003, 138, 1249–1252. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  139. Chegini, N.; Kotseos, K.; Zhao, Y.; Bennett, B.; McLean, F.W.; Diamond, M.P.; Holmdahl, L.; Burns, J. Differential expression of TGF-β1 and TGF-β3 in serosal tissues of human intraperitoneal organs and peritoneal adhesions. Hum. Reprod. 2001, 16, 1291–1300. [Google Scholar] [CrossRef] [Green Version]
  140. Freeman, M.L.; Saed, G.M.; Elhammady, E.F.; Diamond, M.P. Expression of transforming growth factor beta isoform mRNA in injured peritoneum that healed with adhesions and without adhesions and in uninjured peritoneum. Fertil. Steril. 2003, 80 (Suppl. 2), 708–713. [Google Scholar] [CrossRef]
  141. Tyrone, J.; Krause, D.K.; Cathrine, J.; Wheeler, S.E.R.D.M. Increased Levels of Surgical Adhesions in TGFbeta1 Heterozygous Mice. J. Investig. Surg. 1999, 12, 31–38. [Google Scholar] [CrossRef] [PubMed]
  142. Tsauo, J.; Song, H.-Y.; Choi, E.Y.; Kim, D.-K.; Kim, K.Y.; Park, J.-H.; Kim, M.T.; Yoo, S.H.; Lim, Y.J. EW-7197, an oral transforming growth factor β type I receptor kinase inhibitor, for preventing peritoneal adhesion formation in a rat model. Surgery 2018, 164, 1100–1108. [Google Scholar] [CrossRef]
  143. Soleimani, A.; Asgharzadeh, F.; Rahmani, F.; Avan, A.; Mehraban, S.; Fakhraei, M.; Arjmand, M.H.; Binabaj, M.M.; Parizadeh, M.R.; Ferns, G.A. Novel oral transforming growth factor-β signaling inhibitor potently inhibits postsurgical adhesion band formation. J. Cell. Physiol. 2020, 235, 1349–1357. [Google Scholar] [CrossRef]
  144. Cahill, R.A.; Redmond, H.P. Cytokine orchestration in post-operative peritoneal adhesion formation. World J. Gastroenterol. 2008, 14, 4861–4866. [Google Scholar] [CrossRef]
  145. Imudia, A.N.; Kumar, S.; Saed, G.M.; Diamond, M.P. Pathogenesis of Intra-abdominal and pelvic adhesion development. Semin. Reprod. Med. 2008, 26, 289–297. [Google Scholar] [CrossRef]
  146. Molinas, C.R.; Binda, M.M.; Koninckx, P.R. Angiogenic factors in peritoneal adhesion formation. Gynecol. Surg. 2006, 3, 157–167. [Google Scholar] [CrossRef] [Green Version]
  147. Futami, R.; Miyashita, M.; Nomura, T.; Makino, H.; Matsutani, T.; Sasajima, K.; Tajiri, T. Increased serum vascular endothelial growth factor following major surgical injury. J. Nippon Med. Sch. 2007, 74, 223–229. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  148. Wiczyk, H.P.; Grow, D.R.; Adams, L.A.; O’Shea, D.L.; Reece, M.T. Pelvic adhesions contain sex steroid receptors and produce angiogenesis growth factors. Fertil. Steril. 1998, 69, 511–516. [Google Scholar] [CrossRef]
  149. Saltzman, A.K.; Olson, T.A.; Mohanraj, D.; Carson, L.F.; Ramakrishnan, S. Prevention of postoperative adhesions by an antibody to vascular permeability factor/vascular endothelial growth factor in a murine model. Am. J. Obs. Gynecol. 1996, 174, 1502–1506. [Google Scholar] [CrossRef]
  150. Molinas, C.R.; Binda, M.M.; Carmeliet, P.; Koninckx, P.R. Role of vascular endothelial growth factor receptor 1 in basal adhesion formation and in carbon dioxide pneumoperitoneum-enhanced adhesion formation after laparoscopic surgery in mice. Fertil. Steril. 2004, 82 (Suppl 3), 1149–1153. [Google Scholar] [CrossRef] [Green Version]
  151. Jelveh Moghaddam, H.; Aghajani, M.; Raeis-Abdollahi, E.; Faghihi, M.; Dabbagh, A.; Imani, A. Decrease in VEGF-Induced Pericardial Adhesion Formation Using Bevacizumab After Surgery. Surg. Innov. 2019, 26, 21–26. [Google Scholar] [CrossRef]
  152. Cheong, Y.C.; Shelton, J.B.; Laird, S.M.; Li, T.C.; Ledger, W.L.; Cooke, I.D. Peritoneal fluid concentrations of matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1, and transforming growth factor-beta in women with pelvic adhesions. Fertil. Steril. 2003, 79, 1168–1175. [Google Scholar] [CrossRef]
  153. Chegini, N.; Kotseos, K.; Bennett, B.; Diamond, M.P.; Holmdahl, L.; Burns, J. Matrix metalloproteinase (MMP-1) and tissue inhibitor of MMP in peritoneal fluids and sera and correlation with peritoneal adhesions. Fertil. Steril. 2001, 76, 1207–1211. [Google Scholar] [CrossRef]
  154. Chegini, N.; Kotseos, K.; Zhao, Y.; Ma, C.; McLean, F.; Diamond, M.P.; Holmdahl, L.; Burns, J. Expression of matrix metalloproteinase (MMP-1) and tissue inhibitor of MMP in serosal tissue of intraperitoneal organs and adhesions. Fertil. Steril. 2001, 76, 1212–1219. [Google Scholar] [CrossRef]
  155. Christodoulidis, G.; Tsilioni, I.; Spyridakis, M.-E.; Kiropoulos, T.; Oikonomidi, S.; Koukoulis, G.; Tepetes, K. Matrix Metaloproteinase-2 and -9 Serum Levels as Potential Markers of Intraperitoneal Adhesions. J. Investig. Surg. 2013, 26, 134–140. [Google Scholar] [CrossRef]
  156. Atta, H.; El-Rehany, M.; Roeb, E.; Abdel-Ghany, H.; Ramzy, M.; Gaber, S. Mutant matrix metalloproteinase-9 reduces postoperative peritoneal adhesions in rats. Int. J. Surgery. 2016, 26, 58–63. [Google Scholar] [CrossRef]
  157. Liu, X.; Wei, Y.; Bai, X.; Li, M.; Li, H.; Wang, L.; Zhang, S.; Li, X.; Zhao, T.; Liu, Y. Berberine prevents primary peritoneal adhesion and adhesion reformation by directly inhibiting TIMP-1. Acta Pharm. Sin. B 2020, 10, 812–824. [Google Scholar] [CrossRef] [PubMed]
  158. Chegini, N.; Zhao, Y.; Kotseos, K.; Ma, C.; Bennett, B.; Diamond, M.P.; Holmdahl, L.; Skinner, K. Differential expression of matrix metalloproteinase and tissue inhibitor of MMP in serosal tissue of intraperitoneal organs and adhesions. BJOG 2002, 109, 1041–1049. [Google Scholar] [CrossRef] [PubMed]
  159. Reed, K.L.; Fruin, A.B.; Gower, A.C.; Stucchi, A.F.; Leeman, S.E.; Becker, J.M. A neurokinin 1 receptor antagonist decreases postoperative peritoneal adhesion formation and increases peritoneal fibrinolytic activity. Proc. Natl. Acad. Sci. USA 2004, 101, 9115–9120. [Google Scholar] [CrossRef] [Green Version]
  160. Reed, K.L.; Fruin, A.B.; Bishop-Bartolomei, K.K.; Gower, A.C.; Nicolaou, M.; Stucchi, A.F.; Leeman, S.E.; Becker, J.M. Neurokinin-1 receptor and substance P messenger RNA levels increase during intraabdominal adhesion formation. J. Surg. Res. 2002, 108, 165–172. [Google Scholar] [CrossRef] [PubMed]
  161. Esposito, A.J.; Heydrick, S.J.; Cassidy, M.R.; Gallant, J.; Stucchi, A.F.; Becker, J.M. Substance P is an early mediator of peritoneal fibrinolytic pathway genes and promotes intra-abdominal adhesion formation. J. Surg. Res. 2013, 181, 25–31. [Google Scholar] [CrossRef]
  162. Cassidy, M.R.; Sheldon, H.K.; Gainsbury, M.L.; Gillespie, E.; Kosaka, H.; Heydrick, S.; Stucchi, A.F. The neurokinin 1 receptor regulates peritoneal fibrinolytic activity and postoperative adhesion formation. J. Surg. Res. 2014, 191, 12–18. [Google Scholar] [CrossRef]
  163. Bi, J.; Zhang, S.; Du, Z.; Zhang, J.; Deng, Y.; Liu, C.; Zhang, J. Peripheral serotonin regulates postoperative intra-abdominal adhesion formation in mice. Sci. Rep. 2017, 7, 10001. [Google Scholar] [CrossRef]
  164. Shavell, V.I.; Saed, G.M.; Diamond, M.P. Review: Cellular metabolism: Contribution to postoperative adhesion development. Reprod. Sci. 2009, 16, 627–634. [Google Scholar] [CrossRef] [PubMed]
  165. Fletcher, N.M.; Jiang, Z.L.; Diamond, M.P.; Abu-Soud, H.M.; Saed, G.M. Hypoxia-generated superoxide induces the development of the adhesion phenotype. Free Radic Biol Med. 2008, 45, 530–536. [Google Scholar] [CrossRef] [Green Version]
  166. Braun, K.M.; Diamond, M.P. The biology of adhesion formation in the peritoneal cavity. Semin. Pediatr. Surg. 2014, 23, 336–343. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  167. Rinkevich, Y.; Mori, T.; Sahoo, D.; Xu, P.X.; Bermingham, J.R., Jr.; Weissman, I.L. Identification and prospective isolation of a mesothelial precursor lineage giving rise to smooth muscle cells and fibroblasts for mammalian internal organs, and their vasculature. Nat. Cell Biol. 2012, 14, 1251–1260. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  168. Rinkevich, Y.; Walmsley, G.G.; Hu, M.S.; Maan, Z.N.; Newman, A.M.; Drukker, M.; Januszyk, M.; Krampitz, G.W.; Gurtner, G.C.; Lorenz, H.P.; et al. Skin fibrosis. Identification and isolation of a dermal lineage with intrinsic fibrogenic potential. Science 2015, 348, aaa2151. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  169. Thakur, M.; Rambhatla, A.; Qadri, F.; Chatzicharalampous, C.; Awonuga, M.; Saed, G.; Diamond, M.P.; Awonuga, A.O. Is There a Genetic Predisposition to Postoperative Adhesion Development? Reprod. Sci. 2020, 1–11. [Google Scholar] [CrossRef]
  170. Gemmati, D.; Occhionorelli, S.; Tisato, V.; Vigliano, M.; Longo, G.; Gonelli, A.; Sibilla, M.G.; Serino, M.L.; Zamboni, P. Inherited genetic predispositions in F13A1 and F13B genes predict abdominal adhesion formation: Identification of gender prognostic indicators. Sci. Rep. 2018, 8, 16916. [Google Scholar] [CrossRef] [PubMed]
  171. Bian, Y.-Y.; Yang, L.-L.; Yan, Y.; Zhao, M.; Chen, Y.-Q.; Zhou, Y.-Q.; Wang, Z.X.; Li, W.L.; Zeng, L. Identification of candidate biomarkers correlated with pathogenesis of postoperative peritoneal adhesion by using microarray analysis. World J. Gastrointest. Oncol. 2020, 12, 54–65. [Google Scholar] [CrossRef] [PubMed]
Table
Table 1. Cellular mediators and their role in adhesion formation.
Table 1. Cellular mediators and their role in adhesion formation.
Cellular TargetRole in Adhesions
Mesothelial CellsLoss of protective mesothelium *
Activated mesothelial cells *
Profibrotic phenotype upon traumatic insult
MMT may be a source of adhesiogenic myofibroblasts
Secrete inflammatory mediators, chemokines, growth factors, and ECM components
Directly recruit neutrophils and monocytes under mechanical stress
Inflammatory mediators promote detachment of mesothelial cells
↑ surface marker mesothelin
Cytoskeletal and calcium-dependent membrane bridges may drive early adhesion formation
Fibroblasts↑ in adhesions correlated with development of vessel structures and long-lasting connective tissue elements
Acquisition of myofibroblast phenotype
Secretion of ECM components
MyofibroblastsStimulated by profibrotic TGF-β
↑ α-SMA expression indicating increased cellular activity and profibrotic response
↑ expression of type I and II collagen, MMP-1, TIMP-1, fibronectin, COX-2, and TGF-β
Hyperplasia
Myofibroblast activation may facilitate transition to dense fibrous adhesions
MacrophagesPredominant cell population after surgical trauma
Unique autocrine activation in response to tissue damage
Identified in long-lasting adhesions
Recruitment of inflammatory cells
Secretion of PA, PAI, IL-1, IL-6, and TNFα
Recruitment of mesothelial cells to injury
M2 macrophage response inversely correlated with peritoneal adhesion formation
NeutrophilsPredominant cell population in early period of adhesion formation
Respond to mesothelial and inflammatory cell
Release IL-8 and IL-1β
Role in TGF-β secretion
Generation of ROS
NET formation contributes to pathogenesis
Reduction or depletion has beneficial effects for reduction of adhesion formation *
Inhibition increases adhesion formation *
T-CellsPredominant cell population on third day after insult
Persist in quality and quantity in mature adhesions
Fibrotic disorders share T-cell abnormalities
Adhesion formation requires of CD4+ αβ T-cells
Production of IL-17, IL-6
IFN-γ and T-bet drives adhesion formation *
Reduction of Th2 and Treg drives adhesion formation *
Th1 CD4+ phenotype drives adhesion formation *
Mast CellsHigh concentrations in adhesion sites
Release histamine, serotonin, cytokines, serine proteases, chymase, and VEGF
Deficient mice demonstrate adhesions
α-SMA = α-smooth muscle actin, COX-2 = cyclooxygenase-2, ECM = extracellular matrix, IL = interleukin, MCP = monocyte chemo-attractant protein, MMP-1 = matrix metalloproteinase-1, MMT = mesothelial-to-mesenchymal transitions, NET = neutrophil extracellular traps, ROS = reactive oxygen species, TIMP-1 = tissue inhibitor of metalloproteinase-1, TGF-β = transforming growth factor-beta, TNFα = tumor necrosis factor-alpha, VEGF = vascular endothelial growth factor, ↑ = increases, * = currently debated in the literature.
Table
Table 2. Soluble mediators and their role in adhesion formation.
Table 2. Soluble mediators and their role in adhesion formation.
Signaling MoleculeBrief Role in Adhesions
FibrinDisruption of fibrin production and fibrinolysis homeostasis
Formation of polymeric matrix for cellular adhesion and ECM production
Scaffold for fibroblasts and capillary formation
↑ plasminogen activation
Tissue plasminogen activator (tPA)Regulation of fibrinolytic system
↓ plasma levels in rat peritoneal adhesion model
Plasminogen activator inhibitor (PAI)Inhibit tissue plasminogen activator, ↓ fibrinolysis
↑ plasma levels in rat peritoneal adhesion model
Reactive Oxygen Species (ROS)Enhanced in peritoneal adhesion
Direct cytotoxic effect on mesothelial cells
Inhibit fibrinolysis through PAI-1 release in mesothelial cells
Treatment by ROS scavengers reduces adhesion formation
ChymaseActivates profibrotic TGF-β
IL-6Marker for early tissue damage
Promotes fibrosis via MMP and TIMP expression
↑ in intra-abdominal adhesion models
↑ in human adhesions 12 h associated with reformation
↑ directly correlated with extent of adhesion formation
Inhibition in mouse model ↓ adhesion formation
Stimulate mesothelial and inflammatory cells to ↑ PAI-1/2
IL-8Neutrophil chemo-attractant
IL-10Modulates macrophage and lymphocyte responses
Inhibit secretion of pro-inflammatory mediators
↑ in adhesion fibroblasts
IL-1Early elevations are biological marker
↑ IL-1 in human adhesions at 48 h
↓ local fibrinolytic capacity
IL-1β increases release of PAI-1 ↓ fibrinolysis
IL-17Peak levels 6–12 h after surgery
↑ IL-17 ↑ PAI-1 and ↓ tPA
IFN-γNecessary for adhesion development
↑ PAI-1 and ↓ tPA
TNF-α↑ directly correlated with extent of adhesion formation
↑ IL production
TGF-βPrincipal fibrotic mediator
↑ in adhesion tissue, peritoneal fluid, and animal models
↓ reduces incidence, quality, and tenacity of adhesions
VEGFIncreases vascular permeability
Promotes deposition of fibrin matrix
↑ in endothelial cells in pelvic adhesions
↓ reduces adhesions
MMP and TIMPMMP-2/9 proposed as biomarkers
MMP/TIMP ratio alterations decrease enzymatic activity
Inactivating MMP results in reduction of severity
Blocking TIMP-1 prevents primary adhesion formation
Substance P↓ fibrinolytic activity
Serotonin↑ inflammation, oxidative stress, angiopoiesis
↑ TGF-β expression
Regulation of fibrinolytic system
ECM = extracellular matrix, IFN-γ = interferon-gamma, IL = interleukin, PAI = plasminogen activator inhibitors, tPA = tissue plasminogen activator, ROS = reactive oxygen species, TGF-β = transforming growth factor-beta, TNFα = tumor necrosis factor-alpha, VEGF = vascular endothelial growth factor, ↑ = increases, ↓ = decreases.
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Fatehi Hassanabad, A.; Zarzycki, A.N.; Jeon, K.; Deniset, J.F.; Fedak, P.W.M. Post-Operative Adhesions: A Comprehensive Review of Mechanisms. Biomedicines 2021, 9, 867. https://doi.org/10.3390/biomedicines9080867

AMA Style

Fatehi Hassanabad A, Zarzycki AN, Jeon K, Deniset JF, Fedak PWM. Post-Operative Adhesions: A Comprehensive Review of Mechanisms. Biomedicines. 2021; 9(8):867. https://doi.org/10.3390/biomedicines9080867

Chicago/Turabian Style

Fatehi Hassanabad, Ali, Anna N. Zarzycki, Kristina Jeon, Justin F. Deniset, and Paul W. M. Fedak. 2021. "Post-Operative Adhesions: A Comprehensive Review of Mechanisms" Biomedicines 9, no. 8: 867. https://doi.org/10.3390/biomedicines9080867

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