Medicinal Herbal Extracts: Therapeutic Potential in Acute Lung Injury

Abstract

Acute lung injury (ALI) is induced by pneumonia, sepsis and other conditions. The disease characteristics include severe lung inflammation, in which various cells, such as epithelial cells, macrophages, and neutrophils, play a pivotal role. Corticosteroids and antibiotics are used to treat ALI; however, they may have side effects. Cumulative data confirm that traditional herbal medicines exert therapeutic effects against endotoxin-induced inflammatory responses in both in vitro and in vivo ALI studies. This review briefly describes the anti-ALI effects of medicinal herbal extracts (MHEs) and their molecular mechanisms, especially focusing on Toll-like receptor 4/nuclear factor kappa B cell pathways, with a brief summary of in vitro and in vivo ALI experimental models. Thus, the present review highlights the excellent potential of MHEs for ALI therapy and prevention and may also be useful for the establishment of in vitro and in vivo ALI models.

1. Introduction

Pneumonia, endotoxemia and other disorders can cause acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) [1]. ARDS is the most severe manifestation of ALI and its severity is associated multiple organ failure and increased mortality [2,3]. The recent coronavirus (SARS-CoV-2) pandemic sharply increased the ALI/ARDS incidence and mortality rates worldwide [4]. Therefore, there is a need to develop drugs and adjuvants to alleviate ALI symptoms and ensure safety. ALI is characterized by the migration of leukocytes (neutrophils and monocytes) into the alveoli, inflammation, injury to the alveolar capillary endothelium, pulmonary edema, and breathing difficulties [5,6,7]. Various cell types such as respiratory epithelial cells, macrophages, and neutrophils promote ALI development by releasing inflammatory molecules [8,9].

Airway epithelial cells (AFCs) facilitate mucociliary clearance and act as major barriers against respiratory pathogens [10,11]. AFCs have Toll-like receptors (TLRs) [12] and TLR4-dependent nuclear factor kappa B (NF-κB) activation in AFCs promotes the expression of cytokines (interleukin [IL]-1β, IL-6 and tumor necrosis factor α [TNF-α]) and chemokines (IL-8 and monocyte chemoattractant protein 1 [MCP-1]) that amplify inflammatory reactions in ALI [13,14,15,16]. Alveolar epithelial cells (ALECs) are also exposed daily to air-containing pathogens [11]. Type I ALECs facilitate gas transport (exchange) [17], whereas type II ALECs play an important role in surfactant formation [18]. Type II ALECs increase the production of cytokines (IL-1β, IL-6, and TNF-α) and the expression of mediators (inducible nitric oxide synthase [iNOS] and cyclooxygenase 2 [COX-2]) in response to lipopolysaccharide (LPS) stimulation [19,20,21]. This reaction proceeds through the upregulation of TLR4 expression and NF-κB activation. ALFC-derived chemokines, such as MCP-1, recruit cells such as macrophages and neutrophils [22]. A reduction in TLR4 and myeloid differentiation primary response 88 (MyD88) activation is accompanied by heme oxygenase 1 (HO-1) upregulation in LPS-stimulated ALECs [19,23,24].

Alveolar macrophages (AMs) are located in the bronchoalveolar space and act as frontline defenders against pulmonary infections [10]. During bacterial infection, AMs are transformed to pro-inflammatory macrophages (M 1 phenotype macrophage) that release pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), chemokines (MCP-1) and mediators (nitric oxide [NO], iNOS, prostaglandin 2 [PGE2], and COX-2) [8,9,25]. This reaction is derived from the activation of the TLR4/MyD88/NF-κB signaling pathway in AMs. Macrophages that differentiated from circulating monocytes participate in ALI when AMs are impaired and promote ALI development by releasing inflammatory molecules (cytokines, chemokines, and mediators) [13,26,27,28]. Excessive production of these molecules eventually causes hyperinflammation, alveolar destruction, and organ dysfunction. Bromodomain-containing protein 4 (BRD4) plays a critical role in the pathogenesis of ALI by regulating NF-κB activation in macrophages [29]. Increased HO-1 expression owing to nuclear factor erythroid 2-related factor 2 (Nrf2) activation ameliorates the LPS-induced inflammatory response in macrophages by reducing TLR4 expression and NF-κB activation [30].

In ALI, circulating neutrophils migrate to the site of infection and release molecules [7]. TLR4 activation in neutrophils leads to nuclear translocation of NF-κB and the formation of cytokines (IL-1β and TNF-α) and chemokines (macrophage inflammatory protein 2 [MIP-2]) [31]. LPS-induced TLR4 activation in neutrophils leads to NADPH oxidase 2/reactive oxygen species (ROS) production, which causes the formation of neutrophil extracellular traps (NETs) [32]. Overzealous neutrophil activation causes lung impairment by hyperproduction of ROS, elastase, and NETs in ALI [33,34,35]. NETs promote AM pyroptosis [13]. Neutrophils have an interdependent relationship with macrophages when they move to areas of pulmonary inflammation [36,37].

Traditional medicines (TMs) in East Asia include traditional Chinese medicine (TCM), traditional Japanese medicine (Kampo), and traditional Korean medicine. Medicinal herbal extracts (MHEs) have been used as TMs to treat pain [38]. Extracts from flowers, fruits, stems, bark, leaves, and roots of plants have been commonly used as herbal soups in Asia for many years [39], and their crude extracts contain phytocompounds that have healing effects with low side effects in various diseases [39,40,41]. In particular, the modulatory effects of MHEs on endotoxin-induced inflammatory molecules (cytokines, chemokines, and mediators) were revealed in various cell types and animal models from 2012 to 2024. In this review, we briefly summarize the ameliorative effects of MHEs and their associated underlying mechanisms, with a brief introduction to in vitro and in vivo ALI models.

2. TLR4/NF-κB Activation in Immune Cells Against Endotoxin-Induced ALI

Overzealous activation of various cells such as epithelial cells, macrophages, and neutrophils causes pulmonary inflammation and impairment in endotoxin-induced ALI (Figure 1).

3. Ameliorative Effects of MHEs in ALI/ARDS Models

To simulate human ALI/ARDS complications, endotoxin LPS is often adapted as an inducer in various cell lines and mice of ALI models [42,43,44]. MHEs suppress LPS-induced NF-κB activation/inflammatory molecule production in various cells such as epithelial cells and macrophages as well as in animal models. We briefly summarized the anti-ALI effects of MHEs based on the experimental results of ALI (

Table 1. Anti-ALI effects of PEs in in vitro ALI models.

RAW264.7 cells (Murine macrophages)
Plant source	POP	Stimulator	Inhibition effect	Reference
Alismatis rhizoma		LPS (0.1 μg/mL)	IL-1β, iNOS, COX-2	[45]
Lysimachia clethroide	Whole	LPS (0.1 μg/mL)	IL-1β, IL-6, NO, iNOS	[46]
Callicarpa japonica	Leaf stem	LPS (0.5 μg/mL)	IL-6, NO, iNOS	[47]
Mahonia bealei	Leaf	LPS (1.0 μg/mL)	TNF-α, NO, PGE2, iNOS, COX-2	[48]
Picrasma quassiodes	Stem bark	LPS (0.5 μg/mL)	L-6, TNF-α, MCP-1	[27]
Viola tianshanica		LPS (1.0 μg/mL)	IL-1β, IL-6, TNF-α, NO, PGE2	[49]
Paulownia tomentosa	Stem bark	LPS (0.5 μg/mL)	IL-6, TNF-α	[50]
Spilanthes acmella	Whole	LPS (1.0 μg/mL)	IL-1β, IL-6, TNF-α	[51]
Ficus vasculosa		LPS (0.5 μg/mL)	IL-1β, IL-6, TNF-α, iNOS, COX-2	[52]
MH-S cells (Murine alveolar macrophages)
Plant source	POP	Stimulator	Inhibition effect	Reference
Angelica decursiva	Root	LPS (0.1 μg/mL)	NO, iNOS	[53]
Bone marrow-derived macrophages
Plant source	POP	Stimulator	Inhibition effect	Reference
Carthamus tinctorius		LPS (0.1 μg/mL)	IL-1β, TNF-α, COX-2	[54]
Impatiens textori	Whole	LPS (10 ng/mL)	IL-1β	[55]
Peritoneal macrophages
Plant source	POP	Stimulator	Inhibition effect	Reference
Cryptotaenia japonica	Aerial	LPS (0.1 μg/mL)	IL-6, IL-12, TNF-α	[56]
Athyrium multidentatum	Aerial	LPS (0.1 μg/mL)	IL-1β, IL-6, TNF-α, NO, PGE2, iNOS, COX-2	[57]
Cardamine komarovii	Flower	LPS (100 g/mL)	NO, PGE2, iNOS, COX-2	[58]
THP-1 cells (Human monocytic cells)
Plant source	POP	Stimulator	Inhibition effect	Reference
Helminthostachys zeylanica	Root	LPS (1 μg/mL)	ICAM-1	[59]
A549 cells (Human alveolar epithelial cells)
Plant source	POP	Stimulator	Inhibition effect	Reference
Angelica decursiva	Root	IL-1β (10 ng/mL)	IL-6	[53]
Helminthostachys zeylanica	Root	LPS (1.0 μg/mL)	IL-6, IL-8, CCL-5, MCP-1	[59]
Ficus vasculosa		LPS (10 μg/mL)	IL-1β, IL-6, TNF-α	[52]

Abbreviations: POP, parts of the plant; PE, plant extract; ALI, acute lung injury; LPS, lipopolysaccharide.

and

Table 2. (a) Anti-ALI effects of PEs in in vivo ALI models. (b) Anti-ALI effects of PEs in in vivo ALI models.

(a)
ICR mice
Plant source	POP	Stimulator	Inhibition effect	Reference
Mosla scabra	Leaf	LPS (0.5 mg/kg)	IL-1β, IL-6, TNF-α, MPO, NO	[60]
Ginkgo biloba	Leaf	LPS (100 μg)	MPO, MDA, MMP-9	[41]
Ginkgo biloba	Leaf	LPS (100 μg)	IL-6, TNF-α, MIP-2, iNOS, COX-2	[61]
Forsythia suspensa	Fruit	LPS (5.0 mg/kg)	IL-1β, IL-6, TNF-α	[62]
BALB/c mice
Plant source	POP	Stimulator	Inhibition effect	Reference
Cryptotaenia japonica	Aerial	LPS (1.3 mg/kg)	IL-6, TNF-α	[56]
Lysimachia clethroide	Whole	LPS (5.0 mg/kg)	IL-6	[46]
Lonicerae japonicae		LPS (100 pg/kg)	IL-6, TNF-α, NO, iNOS	[63]
Taraxacum mongolicum			IL-6, TNF-α, MPO	[64]
Impatiens textori	Whole	LPS (5.0 mg/kg)	IL-1β	[55]
Helminthostachys zeylanica	Root	LPS (1.0 μg/mL)	IL-1β, IL-6, TNF-α, CCL-5, MCP-1, ICAM-1	[59]
Viola tianshanica		LPS (300 μg)	IL-6, TNF-α	[49]
Athyrium multidentatum	Aerial	LPS (5.0 mg/kg)	IL-1β, IL-6, TNF-α, NO	[57]
Rhaponticum uniflorum		LPS (5.0 mg/kg)	IL-6, TNF-α, MDA, iNOS, COX-2	[65]
Quercus coccinea	Leaf	LPS (10 mg/kg)	IL-1β, TNF-α, HMGB-1	[66]
Corydalis bungeana	Whole	LPS (5.0 mg/kg)	IL-1β, IL-6, IL-18	[67]
(b)
C57BL/6 mice
Plant source	POP	Stimulator	Inhibition effect	Reference
Alismatis rhizoma		LPS (0.01 g/kg)	IL-1β, iNOS, COX-2	[45]
Callicarpa japonica	Leaf stem	LPS (20 μg)	IL-6, iNOS	[47]
Mahonia bealei	Leaf	LPS (10 μg)	IL-6, TNF-α	[48]
Picrasma quassiodes	Stem bark	LPS (10 μg)	L-6, TNF-α, iNOS	[27]
Paulownia tomentosa	Stem bark	LPS (10 μg)	IL-6, TNF-α, MCP-1, iNOS, ROS	[50]
Spilanthes acmella	Whole	LPS (2.0 mg/kg)	IL-1β, IL-6, TNF-α, MPO	[51]
Thalictrum minus	Aerial	LPS (5.0 mg/kg)	IL-1β, TNF-α, NO	[68]
Lagerstroemia ovalifolia	Leaf	LPS (0.5 mg/kg)	IL-6, TNF-α, MCP-1, iNOS, COX-2	[69]
Ficus vasculosa		LPS (0.5 mg/kg)	IL-1β, IL-6, TNF-α, MCP-1	[52]
Platycodon grandiflorum	Root	LPS (3.0 mg/kg)	IL-1β, IL-6, TNF-α	[70]
Kunming mice
Plant source	POP	Stimulator	Inhibition effect	Reference
Hippophae rhamnoides	Berry	LPS (10 mg/kg)	IL-6, TNF-α, ICAM-1	[71]
Sprague Dawley (SD) rats
Plant source	POP	Stimulator	Inhibition effect	Reference
Atractylodis rhizome		LPS (5.0 mg/kg)	IL-1β, IL-6, TNF-α, MCP-1	[72]

Abbreviations: POP, parts of the plant; PE, plant extract; ALI, acute lung injury; LPS, lipopolysaccharide.

).

3.1. Cryptotaenia japonica (2012)

The methanol aerial extract (MAE, 100 and 200 μg/mL) of C. japonica, which is distributed in China, Japan, and Korea, exerted inhibitory effects in LPS (100 ng/mL)-induced IL-6/IL-12/TNF-α secretion and activation of inhibitor of nuclear factor kappa B (IκB) and mitogen-activated protein kinases (MAPKs), such as Jun N-terminal kinase (JNK), p38, and extracellular signal-regulated kinase (ERK), in peritoneal macrophages (PM) [56]. To examine the anti-ALI effect of C. japonica MAE, intraperitoneal injection of LPS (1.3 mg/kg) was administered in BALB/c; the significant upregulation of IL-6 and TNF-α, which are important ALI markers, was confirmed in LPS-induced ALI mice. This upregulation was reduced by oral gavage of C. japonica MAE (100 and 400 mg/kg).

3.2. Alismatis Rhizoma (2013)

Han et al. (2013) confirmed that pretreatment with 10 μg/mL of the ethanol extract (EE) of A. Rhizoma (AR), which is used as a TM in China and Korea [45], significantly decreased IL-1β/iNOS/COX-2 mRNA expression and NF-κB activity in 0.1 μg/mL LPS-stimulated RAW264.7 cells (murine macrophage cell line) [45]. Moreover, AR EE notably increased NAD(P)H quinone oxidoreductase 1 (NQO1)/HO-1 mRNA expression, a known antioxidant protein, in mouse macrophage RAW264.7 cells. In an in vivo study, oral gavage of AR EE (0.3 or 1.2 g/kg) exerted an ameliorative effect on the recruitment of neutrophils and IL-1β/iNOS/COX-2 mRNA expression in the lungs of C57BL/6 mice with LPS (0.01 g/kg, i.n.)-induced ALI. Furthermore, AR EE upregulated NQO1/HO-1 mRNA expression in LPS-stimulated ALI mice.

3.3. Mosla scabra (2013)

Mosla scabra (MS) is a medicinal herb with apigenin, acacetin, and magnosalin as its main compounds [73,74]. The protective effects of MS have been confirmed in ALI mice [60]. Chen et al. (2013) revealed that oral administration (30 or 90 mg/kg) of MS ethanol leaf extract (ELE) ameliorated upregulation of the wet-to-dry weight (W/D) ratio in the lung, protein contents and myeloperoxidase (MPO) activity in bronchoalveolar lavage (BAL) fluid, and IL-1β/IL-6/TNF-α/NO formation in the serum of LPS (0.5 mg/kg, intraperitoneal [i.p.])-treated ICR mice. In addition, MS ELE exerted inhibitory effects on IκB degradation, NF-κB p65 nuclear translocation and p-p38 activation. Generally, these effects were comparable with those of i.p. administration of 10 mg/kg dexamethasone (DEX), which was used as a positive control.

3.4. Lysimachia clethroides (2013)

The whole plant extract (WPE) of L. clethroides (LC) showed ameliorative effects in in vitro and in vivo ALI models [46]. Shim et al. (2013) showed that LC WPE (200 μg/mL) had reductive effects on the generation of IL-6/NO, the expression of IL-1β/iNOS, and the activation of interferon regulatory factor 3 (IRF3)/signal transducer and activator of transcription (STAT)1 in LPS (100 ng/mL)-stimulated RAW264.7 cells. In a BALB/c mouse model of LPS (5 mg/kg, i.n.)-induced ALI, LC WPE (100 mg/kg, i.p.) significantly reduced neutrophil influx and IL-6 formation in BAL fluid.

3.5. Ginkgo biloba (2013 and 2014)

Ginkgo biloba (GB) is the maiden hair tree and the most popular herb in TCM. GB leaves contain quercetin, kaempferol, ginkgolides, and bilobalide [41]. Huang et al. (2013) demonstrated the anti-inflammatory effects of GB leaves in an in vivo study on ALI [41]. Intratracheal (i.t.) administration of LPS (100 μg, per mouse) into ICR mice caused remarkable upregulation of protein contents/cells in BAL fluid and MPO/malondialdehyde (MDA)/matrix metalloproteinase 9 formation in lungs. However, i.p. injection (100 or 1000 μg/kg) of GB leaf extract (LE) significantly decreased this upregulation. Furthermore, GB LE effectively suppressed LPS-induced NF-κB p65 activation and IκB degradation in ALI mice. The ameliorative effects of GB LE on LPS-induced inflammatory responses were similar to those of 1 mg/kg DEX.

Lee et al. (2014) confirmed the ameliorative effect of GB LE on the development of ALI in vivo [61]. Administration of GB LE (10, 100 and 1000 μg/kg i.p.) significantly decreased the number of neutrophils and the formation of IL-6/TNF-α/MIP-2 in the BAL fluid of ICR mice with LPS (100 μg, per mouse)-induced ALI. GB LE effectively reduced the expression of iNOS/COX-2 and the activation of IκB in the lungs of ALI mice. Similar to the results reported by Huang et al. (2013) [41], the ameliorative effect of 1000 μg/kg GB LE was comparable with that of 1000 μg/kg DEX.

3.6. Angelica decursiva (2014)

The ethanol root extract (ERE) of A. decursiva (AD) exerted anti-ALI effects in both in vitro and in vivo studies [53]. The experimental results showed that AD ERE (100 μg/mL) significantly suppressed LPS (0.1 μg/mL)-induced NO formation/iNOS expression in mouse alveolar macrophage MH-S cells and IL-1β (10 ng/mL)-induced IL-6 production in A549 human lung alveolar epithelial cells. In addition, anti-ALI effects were demonstrated in ICR mice treated with LPS, which suppressed cell recruitment.

3.7. Carthamus tinctorius (2014)

Carthamus tinctorius (CT), known as Carthami Flos, is used as a TM, and its alleviation of pulmonary inflammation was evaluated in an experimental ALI model [54]. Kim et al. (2014) determined that hydroxysafflor yellow A and kaempferol 3-O-rutinoside were the main constituents of CT aqueous extract (AE) [54]. In in vitro studies, 20 μg/mL CT AE increased Nrf2 activation and HO-1/NQO1/glutamate-cysteine ligase catalytic subunit (GCLC) mRNA expression in bone marrow-derived macrophages (BMDM). CT AE (20 μg/mL) also inhibited LPS (100 ng/mL)-induced NF-κB p65 nucleus translocation and IL-1β/TNF-α/COX-2 in BMDMs. In an in vivo model, CT AE (1.5 or 7.5 mg/kg) outstandingly suppressed the number of neutrophils in BAL fluid and IL-1β/TNF-α mRNA expression in the lungs of C57BL/6 mice with LPS (100 mg/kg, i.n.)-induced ALI. Furthermore, hematoxylin and eosin (H&E) staining showed that LPS-induced cell influx into the lungs was ameliorated by CT AE administration.

3.8. Lonicerae japonicae flos (2015)

Lonicerae japonicae (LJ), known as Jinyinhua, is traditionally used as a medicinal herb in China [63]. Oral administration of LJ AE (4 or 40 mg/kg) significantly ameliorated the formation of IL-6/TNF-α/NO in BAL fluid and the increase in NF-κB activity/MAPK phosphorylation (p38 and JNK) in the lungs of LPS (100 pg/kg, i.t.)-exposed BALB/c mice [63]. The suppressive effects of LJ AE on LPS-induced cell influx into the lungs were demonstrated by H&E staining.

3.9. Taraxacum mongolicum (2015)

Ma et al. (2015) confirmed the in vivo anti-ALI effects of T. mongolicum (TM) in endotoxin-induced ALI [64]. In this study, chlorogenic acid, caffeic acid, and taraxasterol were identified in TM water extract (WE). Oral administration of TM WE suppressed neutrophil numbers and increased superoxide dismutase (SOD) activity in BALB/c mice exposed to LPS. Moreover, upregulation of IL-6/TNF formation in BAL fluid and MPO activity/edema/cell influx in the lungs were reduced by TM WE. These effects were accompanied by reduced phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian targets of rapamycin activation. Overall, the effects of 10 g/kg TM WE were similar to those of the positive control DEX (2 mg/kg).

3.10. Impatiens textori (2015)

The anti-inflammatory effects of the WPE of I. textori (IT), a traditional medicinal herb, was evaluated in ALI experimental models [55]. In vitro results indicated that 100 μg/mL IT WPE attenuated IL-1β formation in LPS (10 ng/mL)-stimulated BMDMs. Moreover, IT WPE inhibited LPS-induced nucleotide-binding domain, leucine-rich-containing family and pyrin domain-containing 3 (NLRP-3) activation in BMDMs. In vivo results proved that i.p. injection of 40 mg/kg IT WPE significantly attenuated cell recruitment, IL-1β formation, and NLRP3 activation in BALB/c mice with LPS (5 mg/kg, i.n.)-induced ALI.

3.11. Callicarpa japonica (2015)

Callicarpa japonica (CJ) is distributed in China and Korea and exerts various biological effects [47]. The anti-ALI effects of CJ methanol leaf stem extract (MLSE) were examined in an ALI experimental mouse model [47]. Two major phenylpropanoids (acteoside and forsythoside B) were detected in the CJ extract by ultra-performance liquid chromatography and quadrupole time-of-flight mass spectrometry analysis. In vitro results showed that CJ MLSE (10, 20, and 40 μg/mL) significantly attenuated LPS (0.5 μg/mL)-induced NO/IL-6 formation in RAW264.7 cells. Moreover, CJ MLSE inhibited iNOS mRNA expression in LPS-stimulated RAW264.7 cells. Furthermore, in vivo results showed that oral gavage of 30 mg/kg CJ MLSE inhibited the number of neutrophils/macrophages and the formation of IL-6 in BAL fluid in a C57LB/9 mouse model of LPS (20 μg, i.n.)-induced ALI. CJ MLSE also suppressed the increased expression of iNOS in the lungs of mice with ALI. The anti-inflammatory properties of 30 mg/kg CJ MLSE were comparable with those of 3 mg/kg DEX.

3.12. Dracocephalum rupestre (2015)

Zhu et al. reported that eriodictyol, a flavonoid from D. rupestre (DR), which is a traditional Chinese herb, attenuated pulmonary inflammation in experimental models of ALI [75]. In that study, eriodictyol downregulated the generation and mRNA expression of IL-1β/IL-6/TNF-α/MIP-2 in LPS-stimulated BMDM. In an in vivo study, 30 mg/kg eriodictyol decreased the generation of IL-1β/IL-6/TNF-α/MIP-2 in the serum and BAL fluid of ALI mice. Eriodictyol also increased the mRNA expression of Nrf2/Trx1 in the lungs of ALI mice.

Wang et al. confirmed the ameliorative effects of eriodictyol in an in vivo study of ALI [76]. It was reported that 80 mg/kg of eriodictyol significantly attenuated the numbers of neutrophils/macrophages and the formation of IL-1β/IL-6/TNF-α/PGE2 in BAL fluids of the ALI group. Eriodictyol also inhibited MPO/MDA upregulation and SOD downregulation in the lungs of the ALI group. This effect was accompanied by its modulatory effects on NF-κB/NLRP3 activation.

3.13. Mahonia bealei (2016)

Mahonia bealei (MB) has long been used in TCM to ameliorate inflammatory diseases [48]. Hu et al. (2016) revealed that the dichloromethane fraction (50 or 100 μg/mL) of MB ELE remarkably suppressed LPS (1 μg/mL)-induced upregulation of TNF-α/NO/PGE2 formation, TNF-α/iNOS/COX-2 mRNA expression, and NF-κB activation in RAW264.7 cells [48]. In addition, MB ELE exerted inhibitory effects on IL-6/TNF-α formation and NF-κB nuclear translocation in the lungs of LPS (10 μg, per mouse)-administered C57BL/6 mice.

3.14. Picrasma quassiodes (2016)

The medicinal herb P. quassiodes (PQ) is used as a TM, and β-carbolines and canthin-6-one alkaloids are the active compounds in PQ [77]. PQ methanol stem bark extract (MSBE) was evaluated for its regulatory effect on ALI progression via in vitro and in vivo studies [27]. The experimental results showed that PQ MSBE (5, 10 and 20 μg/mL) significantly suppressed the formation of IL-6/TNF-α, the mRNA expression of MCP-1, and the activation of p38/NF-κB in LPS (0.5 μg/mL)-stimulated RAW264.7 cells. PQ MSBE upregulated the activation of Nrf2 and the expression of HO-1 in RAW264.7 cells. Furthermore, oral gavage (15 mg/kg) of PQ MSBE inhibited the increased levels of immune cells (neutrophils/macrophages), cytokines (IL-6/TNF-α), mediators (iNOS), and p38/p65 phosphorylation in the lungs of LPS (10 μg, i.n.)-exposed C57BL/6 mice. The anti-inflammatory effects of PQ MSBE on endotoxin-induced pulmonary inflammation in vivo were similar to that of 3 mg/kg DEX.

3.15. Helminthostachys zeylanica (2017)

Helminthostachys zeylanica (HZ) is a medicinal herb that is used to treat inflammatory diseases [59]. The protective effects of HZ water root extract (WRE) were evaluated in an ALI experimental model [59]. The results from the in vitro studies indicated that HZ WRE (1, 5 and 10 μg/mL) inhibited LPS (1 μg/mL)-induced IL-6/IL-8/C-C motif chemokine ligand 5 (CCL-5)/MCP-1 formation in A549 cells and LPS (1 μg/mL)-induced intercellular adhesion molecule 1 (ICAM-1) formation in THP-1 cells. In LPS (1 μg/mL, i.t.)-induced ALI BALB/c mice, oral gavage of HZ WRE (10 mg/kg) significantly downregulated the increase in neutrophil numbers and IL-6/TNF-α formation in BAL fluid and remarkably suppressed IL1β/IL-6/TNF-α/CCL-5/MCP-1/ICAM-1/iNOS/COX-2 mRNA expression in the lung. HZ WRE (10 mg/kg) also caused downregulation of the W/D ratio and MPO/MDA activity and upregulation of reduced glutathione (GSH)/SOD activity in the lungs of ALI mice. Furthermore, HZ WRE decreased IκB/NF-κB and ERK/p38/JNK activation and increased HO-1 expression in ALI mice.

3.16. Viola tianshanica (2017)

Viola tianshanica (VT), known as binafuxi, is used as a herbal medicine by Uyghurs to improve pneumonia [49]. VT EE (25, 50 and 100 μg/mL) significantly attenuated the formation of cytokines (IL-1β, IL-6, and TNF-α)/mediators (NO and PGE2) and the activation of ERK/IκB in LPS (1 μg/mL)-stimulated RAW 264.7 cells [49]. In addition, intragastric administration (250 and 500 mg/kg) of VT EE exerted protective effects on LPS (300 μg, i.n.)-induced pulmonary inflammation in BALB/c mice showing its inhibitory effect on macrophage/neutrophil influx and IL-6/TNF-α formation.

3.17. Paulownia tomentosa (2018)

Paulownia tomentosa (PT) has been used as a medicinal plant for the treatment of various diseases, such as hemorrhoids and gonorrhea [50]. Verbascoside and isoverbascoside have been identified as the predominant compounds in the MSBE of PT [50]. Lee et al. (2018) confirmed the anti-inflammatory effects of PT MSE in an ALI experimental model [50]. Moreover, PT MSBE (20, 40, and 80 μg/mL) significantly mitigated LPS (500 ng/mL)-induced IL-6/TNF-α formation in RAW264.7 cells. In vivo results showed that oral administration of PT MSBE (20 and 40 mg/kg) significantly attenuated the increased levels of neutrophil/macrophage numbers, ROS/IL-6/TNF-α formation in BAL fluid, NO generation in serum, and iNOS/MCP-1/phosphorylated (p)-IκB/p-NF-κB expression in the lungs of LPS (10 μg per mouse, i.n)-induced ALI C57BL/6 mice. PT MSBE also inhibited LPS-induced SOD-3 reduction. The anti-inflammatory effects of 40 mg/kg PT MSBE were similar to those of 1 mg/kg DEX, which was used as the positive control.

3.18. Spilanthes acmella (2018)

The methanolic whole-plant extract (MWPE) of S. acmella (SA) was evaluated for its ameliorative effects on endotoxin-induced inflammatory responses in both in vitro and in vivo ALI studies [51]. In in vitro studies, SA MWPE (30 and 50 μg/mL) diminished IL-1β/IL-6/TNF-α mRNA expression and the nuclear translocation of NF-κB in LPS (1 μg/mL)-stimulated RAW264.7 cells. In addition, 50 μg/mL SA MWPE outstandingly upregulated the activation of Nrf2 and HO-1/NQO1/GCLC mRNA expression in RAW264.7 cells. In in vivo studies, SA MWPE (10 mg/kg, i.t) notably inhibited the LPS (2 mg/kg, i.t.)-induced upregulation of IL-1β/IL-6/TNF-α mRNA expression and MPO activity in the lungs of C57BL/6 mice.

3.19. Athyrium multidentatum (2018)

Han et al. (2018) examined the inhibitory effect of the ethanol aerial part extract (EAPE) of A. multidentatum (AM) on LPS-induced generation of inflammatory molecules in an in vitro study [57]. Moreover, AM EAPE (25, 50 and 100 μg/mL) reduced NO/PGE2 formation, iNOS/COX-2/IL-1β/IL-6/TNF-α production, and ERK/JNK/IRF3/STAT1/STAT3 activation in LPS (0.1 μg/mL)-stimulated PMs isolated from C57BL/6 mice. Based on the in vitro results, they evaluated the anti-ALI effects of AM EAPE in vivo. The results showed that 10 mg/kg AM EAPE significantly mitigated the increase in cell numbers, NO formation, and IL-1β/IL-6/TNF-α formation in LPS (5 mg/kg, i.t.)-exposed BALB/c mice. This inhibitory effect was similar to that of 10 mg/kg DEX.

3.20. Cardamine komarovii (2019)

Cardamine komarovii (CK) is distributed in Korea and China, and its flowers are used as medicinal plants [58]. Qi et al. demonstrated the anti-AD effects of CK flower extract (FE) both in vitro and in vivo [58]. Myricetin and quercetin were found to be the main flavonoids in CK FE. In the in vitro study, CK FE attenuated the secretion of NO/PGE2 and the expression of iNOS/COX-2 in LPS (100 ng/mL)-stimulated PMs. CK FE also exerted inhibitory effects on LPS-induced upregulation of IL-1β/IL-6/TNF-α mRNA expression and p38/NF-κB/IFR3/STAT1/STAT3 activation in PMs. In in vivo experiments, 10 mg/kg CK FE significantly reduced the number of neutrophils in the BAL fluid of ALI mice. In addition, histological analysis revealed that CK FE inhibited cell influx into the lungs.

3.21. Thalictrum minus (2020)

The medicinal herb T. minus has been used to treat pulmonary inflammation [68]. Badamjav et al. (2020) examined the anti-inflammatory effects of 40 mg/kg T. minus aqueous aerial extract (AAE) on LPS (5 mg/kg, i.t.)-induced ALI C57BL/6 mice [68]. The extract significantly suppressed the increased lung injury score and high protein content/macrophages/IL-1β/TNF-α/NO in the BAL fluid of ALI mice. The extract also suppressed the decrease in SOD3 levels in the BAL fluid of ALI mice. Mechanistically, the extract exerted a regulatory effect on LPS-induced activation of p38/NLRP3/caspase-1. Furthermore, it increased AMP-activated protein kinase activation/Nrf2 expression in the lungs of ALI mice.

3.22. Rhodiola rosea (2020)

Zheng et al. reported that Salidroside, known as an active component of R. rosea (RR), inhibited the formation of IL-1β/IL-6/IL-8/TNF-α and the activation of NF-κB in LPS-stimulated AMs [78]. Salidroside also exerted inhibitory effects on IL-1β/IL-6/IL-8/TNF-α formation and NF-κB activation in an in vivo study of ALI. Studies have highlighted its potential application in ARDS therapy [79,80].

3.23. Lagerstroemia ovalifolia (2021)

Lagerstroemia ovalifolia (LO) is an Indonesian plant of the Lythraceae family and is used as a traditional herbal medicine (THM) [69]. Oral gavage of 10 or 20 mg/kg LO methanol leaf extract (MLE) exerts an ameliorative effect on LPS (0.5 mg/kg, i.n.)-induced lung inflammation in C57BL/6 mice, mitigating the increased levels of macrophages/IL-6/TNF-α (BAL fluid) and iNOS/COX-2/MCP-1 (lung). These effects were accompanied by its inhibitory effect on MAPK (ERK/p38/JNK) and NF-κB (p65/IκB) activation. Interestingly, the ameliorative effect of 20 mg/kg LO MLE on LPS-induced lung inflammation was comparable with that of 1 mg/kg DEX alone. Furthermore, 20 mg/kg LO MLE exerted antioxidant effects by upregulating HO-1 expression in mice with ALI.

3.24. Forsythia suspensa (2022)

Wang et al. (2022) recently evaluated the relief effects of the fruit of F. suspenae (FS), which is used as a herbal medicine, on LPS (5 mg/kg, i.t.)-induced pulmonary inflammation in ICR mice [62]. Pinoresinol-4-O-glucoside, forsythiaside A, forsythin, and phillygenin were detected as the active compounds in FS fruit. In in vivo studies, the notable upregulation of IL-1β/IL-6/TNF-α mRNA and TLR/MyD88/Iκκ-B/p-IκB/p-p65/p-p38/p-JNK/p-ERK expression was confirmed in the lungs of mice with LPS-induced ALI. Interestingly, 0.75, 1.5, and 3 g/kg FS methanolic fruit extract (MFE) reduced this increase.

3.25. Rhaponticum uniflorum (2022)

The EE of R. uniflorum (RU) mitigates LPS-induced ALI [65]. Zhen et al. (2022) revealed that the oral administration of RU EE (100, 200, and 400 mg/kg) alleviated lung injury by attenuating cell influx and F4/80 expression in mice with ALI induced by 5 mg/kg LPS aspiration. RU EE downregulates the generation of IL-6/TNF-α/NO in BAL fluid and the expression of IL-6/TNF-α/iNOS/COX-2 in the lungs of ALI mice. RU EE also inhibited the upregulation of LPS-induced MPO activity in both BAL fluid and lungs. Furthermore, RU EE suppressed the reduction in SOD3/catalase/GSH-peroxidase activity and upregulation of MDA activity in the lungs of ALI mice. These effects of RU EE are associated with its modulatory effects on LPS-induced activation of MAPK (p-38/ERK/JNK) and TLR4 (MyD88/IκB/NF-κB) signaling pathways. Moreover, RU EE increased Nrf2/HO-1/NQO1 expression in the lungs of ALI mice. The pharmacological effects of 400 mg/kg RU EE were comparable with those of 5 mg/kg DEX.

3.26. Hippophae rhamnoides (2022)

Hippophae rhamnoides (HR) berries have long been used in traditional Tibetan medicine to treat pulmonary diseases [71]. Bioactive components such as vitamins and fatty acids have been identified in HR. Du et al. (2022) demonstrated the suppressive effects of HR berry extract (BE) on LPS-induced lung inflammation in an in vivo ALI study [71]. HR BE (120, 240, and 480 mg/kg) inhibited cell influx and cytokine production in Kunming mice exposed to LPS (10 mg/kg, i.p.). A significant increase in neutrophils (BAL fluid), IL-6/TNF-α (serum), and NF-κB/ICAM-1/CD62 expression (lung) in the ALI group was reduced by HR BE treatment. The inhibitory ability of 480 mg/kg HR BE on LPS-induced IL-6/TNF-α was similar to that of 1 mg/kg DEX.

3.27. Ficus vasculosa (2022)

Ficus vasculosa (FV) is used as a THM in Southeast Asia, and the protective effects of FV methanol extract (ME) on endotoxin-caused pulmonary inflammation was confirmed in both in vitro and in vivo studies [52]. Park (2022) revealed that 20 μg/mL FV ME remarkably exerted suppressive effects on MAPK/NF-κB activation as well as IL-1β/IL-6/TNF-α/MCP-1/NO/PGE2 formation and iNOS/COX-2 expression in LPS (0.5 μg/mL)-stimulated RAW264.7 cells, with an inhibitory effect on IL-1β/IL-6/TNF-α formation in LPS (10 μg/mL)-stimulated A549 cells. The in vivo results indicated that oral gavage of FV ME (15 mg/kg) significantly suppressed the formation of IL-1β/IL-6/TNF-α in BAL fluid in LPS (0.5 mg/kg, i.n.)-treated C57BL/6 mice. This effect was similar to that observed with 1 mg/kg DEX treatment.

3.28. Azadirachta indica (2022)

A. indica (AI), known as Neem, is commonly distributed in Southeast Asia and was traditionally used for the treatment of inflammatory diseases [81]. A recent report highlights the potential of compounds from AI extracts as an antiviral agent against SARS-CoV-2 [82,83,84]. In that study, AI compounds exhibited moderated inhibitory activity against Papain-like protease (PLpro) of SARS-CoV-2. Desacetylgedunin (DCG) indicated the highest affinity for PLpro [84]. Furthermore, a previous study showed that nimbolide (1 μM), the active compound in AI, outstandingly inhibits NO/iNOS upregulation and HO-1/SOD1 downregulation in LPS-stimulated RAW264.7 and THP-1 cells [85]. In addition, nimbolide suppressed the LPS-caused NF-κB activation in LPS-stimulated A549 cells. In that study, 3 mg/kg nimbolide considerably inhibited the numbers of neutrophils/macrophages in BAL fluid and the expressions of IL-1β/IL-6/TNF-α/TGF-β/MIP-1α/MIP-1β in the lungs of LPS-challenged mice. Nimbolide also downregulated NO/iNOS expression, upregulated HO-1/SOD1 expression and inhibited NF-κB activation in the lungs of the LPS group. A recent observation emphasized that nimbolide may protect against SARS-CoV-2-associated ARDS [86]. In that study, iRGD-conjugated nimbolide liposomes (iRGD-NIMLip) inhibited the expression of iNOS/COX-2/HIF-1α, the activation of NF-κB and the reduction in HO-1/SOD1 in LPS-stimulated macrophages. iRGD-NIMLip also suppressed the activation of AKT/STAT3 in LPS-stimulated bronchial epithelial cells. In addition, the inhibitory ability of 0.3 mg/kg iRGD-NIMLip on immune cell influx was superior to that of 0.3 mg/kg DEX, which was used as a positive control in the ARDS models. These data suggest AI may be valuable candidate for SARS-CoV-2-associated ARDS.

3.29. Platycodon grandiflorum (2023)

The aqueous root extract (ARE) of P. grandiflorum (PG), an important TCM, was evaluated for its ability to prevent endotoxin-induced ALI in mice [70]. To assess the degree of cell influx and mRNA expression of cytokines, H&E staining and reverse transcription PCR analysis were used; the results showed that i.t. administration of 3 mg/kg LPS caused notable recruitment of cells and significant upregulation of IL-1β/IL-6/TNF-α mRNA expression in the lungs of C57BL/6 mice. This tendency was reversed by the administration of PG ARE (7.55 g/kg) and DEX (10 mg/kg). Upon studying the molecular mechanisms, remarkable upregulation of PI3K expression and AKT activation was confirmed in the lungs of the ALI group using Western blot analysis, which was suppressed in the lungs of the PG ARE (7.55 g/kg)-treated ALI group. Furthermore, the significant increase in B-cell lymphoma 2 (BCL2) reduction and BCL-2-like protein 4 upregulation in the lungs of the ALI group was ameliorated by PG ARE treatment.

3.30. Atractylodis rhizome (2023)

Shi et al. (2023) evaluated the therapeutic effect of A. rhizome, a TCM, on pulmonary inflammation in an experimental Sprague Dawley (SD) rat model of LPS-induced ALI (5 mg/kg, i.t.) [72]. Nineteen compounds, including chlorogenic acid, ferulic acid, and atractylodin, were identified in A. rhizome EE (AREE). In ALI animal models, the outstanding increase in cell influx and cytokine (IL-1β, IL-6, and TNF-α)/chemokine (MCP-1) production was confirmed by H&E staining and enzyme-linked immunosorbent assay, respectively [72]. This upregulation was blocked by oral administration of AREE (314.7 and 2517.4 mg/kg) or DEX (5 mg/kg). High-dose AREE showed a similar improvement in pulmonary inflammation as DEX.

3.31. Quercus coccinea (2023)

The protective effects of Q. coccinea (QC) aqueous leaf extract (ALE) on lung inflammation was confirmed in ALI mice [66]. El-Sayed et al. (2023) confirmed various polyphenolic compounds, such as tannins, flavones, and flavonol glycosides, in QC ALE. The in vivo results showed that QC ALE (250, 500, and 1000 mg/kg, p.o.) inhibited LPS (10 mg/kg, i.p.) by suppressing MDA and upregulating GSH/SOD in the lungs of BALB/c mice. In addition, QC ALE decreased not only IL-1β/TNF-α/high mobility group box 1 protein production but also TRL4/MyD88/interleukin-1 receptor-associated kinase 1 expression in the lungs of ALI mice. In this model, the inhibitory effect of QC ALE on cell influx and NF-κB activation was confirmed using H&E and immunohistochemical staining, respectively. In general, the effects of 500 mg/kg QC ALE were comparable with those of DEX (5 mg/kg, p.o.). However, the ameliorative effects in the 500 mg/kg QC ALE-treated group on LPS-induced downregulation of GSH/SOD were better than those in the 5 mg/kg DEX group.

3.32. Corydalis bungeana (2024)

Corydalis bungeana (CB) is used as a TM to ameliorate respiratory infections [67]. Intragastric administration of CB WPE (1 g/kg) decreased the formation of IL-1β/IL-6/IL-18 in both the sera and BAL fluid of LPS (5 mg/kg, i.p.)-treated BALB/c mice [67]. In addition, H&E staining revealed the inhibitory effects of CB WPE on LPS-induced cell influx. Acetylcorynoline is the main alkaloid component of CB WPE.

4. Conclusions

This review describes the anti-ALI effects of herbal plant extracts from different plant parts. Specifically, the modulatory effects of herbal plant extracts on the activation of NF-κB and the formation of inflammatory molecules are noteworthy. Additionally, some of these effects were similar to those of the positive control, DEX. Thus, herbal plant extracts may be considered as an adjuvant candidate for ALI therapy. Additional mechanistic research and safety assurance will facilitate this development.