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Special Issue "Acute Lung Injury – New Insights into the Mechanisms and Emerging Therapies"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 29 October 2019

Special Issue Editor

Guest Editor
Prof. Anna K. Kurdowska

University of Texas Health Center at Tyler, Biomedical Research, Tyler, United States
E-Mail
Interests: inflammation; pro-inflammatory cells; mediators of inflammation; innate immunity; cell signaling; signal transduction; lung disease

Special Issue Information

Dear Colleagues,

Acute lung injury (ALI) and its more severe form termed acute respiratory distress syndrome (ARDS) are complex clinical syndromes associated with uncontrolled systemic inflammatory response. Resulting microvascular damage prompts a substantial increase in both pulmonary vascular and epithelial permeability. Subsequently, airspaces becomes flooded with protein-rich edema fluid leading to acute respiratory failure. The causes of ALI include pulmonary and extra-pulmonary infections and serious conditions such as sepsis, pancreatitis, trauma, pneumonia, and aspiration. ALI and ARDS affect approximately 150,000 people in the United States each year, and the mortality of more severe cases remains at 30–50%. Current therapies are primarily supportive and focus on treatment of the underlying condition along with mechanical ventilation and corticosteroid administration. Most of the research into ALI pathogenesis and treatment has evolved around identifying causative and prognostically important biomarkers. The underling objective has been to find mediators responsible for the development of ALI and progression to ARDS, with an ultimate goal of facilitating the diagnosis of ALI in patients before onset of ARDS. However, prognosis of ALI and ARDS saw only modest improvements which were almost exclusively based on better supportive care.

This Special Issue of the International Journal of Molecular Sciences will focus on recent developments in the area of ALI pathogenesis and treatment, including new insights into the mechanisms and emerging therapies for ALI and ARDS. It will cover a selection of recent research topics and current review articles in the field of ALI and ARDS. Experimental papers, up-to-date review articles, and commentaries are all welcome.

Prof. Anna K. Kurdowska
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • acute lung injury (ALI)
  • acute respiratory distress syndrome (ARDS)
  • inflammation
  • biomarkers
  • molecular pathway
  • therapeutics

Published Papers (3 papers)

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Research

Open AccessCommunication
A Peptide Inhibitor of NADPH Oxidase (NOX2) Activation Markedly Decreases Mouse Lung Injury and Mortality Following Administration of Lipopolysaccharide (LPS)
Int. J. Mol. Sci. 2019, 20(10), 2395; https://doi.org/10.3390/ijms20102395
Received: 28 March 2019 / Revised: 9 May 2019 / Accepted: 11 May 2019 / Published: 15 May 2019
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Abstract
We have previously derived three related peptides, based on a nine-amino acid sequence in human or rat/mouse surfactant protein A, that inhibit the phospholipase A2 activity of peroxiredoxin 6 (Prdx6) and prevent the activation of lung NADPH oxidase (type 2). The present [...] Read more.
We have previously derived three related peptides, based on a nine-amino acid sequence in human or rat/mouse surfactant protein A, that inhibit the phospholipase A2 activity of peroxiredoxin 6 (Prdx6) and prevent the activation of lung NADPH oxidase (type 2). The present study evaluated the effect of these Prdx6-inhibitory peptides (PIP) in a mouse (C57Bl/6) model of acute lung injury following lipopolysaccharide (LPS) administration. All three peptides (PIP-1, 2 and 3) similarly inhibited the production of reactive O2 species (ROS) in isolated mouse lungs as detected by the oxidation of Amplex red. PIP-2 inhibited both the increased phospholipase A2 activity of Prdx6 and lung reactive oxygen species (ROS) production following treatment of mice with intratracheal LPS (5 µg/g body wt.). Pre-treatment of mice with PIP-2 prevented LPS-mediated lung injury while treatment with PIP-2 at 12 or 16 h after LPS administration led to reversal of lung injury when evaluated 12 or 8 h later, respectively. With a higher dose of LPS (15 µg/g body wt.), mortality was 100% at 48 h in untreated mice but only 28% in mice that were treated at 12–24 h intervals, with PIP-2 beginning at 12 h after LPS administration. Treatment with PIP-2 also markedly decreased mortality after intraperitoneal LPS (15 µg/g body wt.), used as a model of sepsis. This study shows the dramatic effectiveness of a peptide inhibitor of Prdx6 against lung injury and mouse mortality in LPS models. We propose that the PIP nonapeptides may be a useful modality to prevent or to treat human ALI. Full article
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Graphical abstract

Open AccessArticle
Essential Role of Visfatin in Lipopolysaccharide and Colon Ascendens Stent Peritonitis-Induced Acute Lung Injury
Int. J. Mol. Sci. 2019, 20(7), 1678; https://doi.org/10.3390/ijms20071678
Received: 11 March 2019 / Revised: 22 March 2019 / Accepted: 27 March 2019 / Published: 4 April 2019
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Abstract
Acute lung injury (ALI) is a life-threatening syndrome characterized by acute and severe hypoxemic respiratory failure. Visfatin, which is known as an obesity-related cytokine with pro-inflammatory activities, plays a role in regulation of inflammatory cytokines. The mechanisms of ALI remain unclear in critically [...] Read more.
Acute lung injury (ALI) is a life-threatening syndrome characterized by acute and severe hypoxemic respiratory failure. Visfatin, which is known as an obesity-related cytokine with pro-inflammatory activities, plays a role in regulation of inflammatory cytokines. The mechanisms of ALI remain unclear in critically ill patients. Survival in ALI patients appear to be influenced by the stress generated by mechanical ventilation and by ALI-associated factors that initiate the inflammatory response. The objective for this study was to understand the mechanisms of how visfatin regulates inflammatory cytokines and promotes ALI. The expression of visfatin was evaluated in ALI patients and mouse sepsis models. Moreover, the underlying mechanisms were investigated using human bronchial epithelial cell lines, BEAS-2B and NL-20. An increase of serum visfatin was discovered in ALI patients compared to normal controls. Results from hematoxylin and eosin (H&E) and immunohistochemistry staining also showed that visfatin protein was upregulated in mouse sepsis models. Moreover, lipopolysaccharide (LPS) induced visfatin expression, activated the STAT3/NFκB pathway, and increased the expression of pro-inflammatory cytokines, including IL1-β, IL-6, and TNF-α in human bronchial epithelial cell lines NL-20 and BEAS-2B. Co-treatment of visfatin inhibitor FK866 reversed the activation of the STAT3/NFκB pathway and the increase of pro-inflammatory cytokines induced by LPS. Our study provides new evidence for the involvement of visfatin and down-stream events in acute lung injury. Further studies are required to confirm whether the anti-visfatin approaches can improve ALI patient survival by alleviating the pro-inflammatory process. Full article
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Figure 1

Open AccessArticle
HER2 Signaling Implicated in Regulating Alveolar Epithelial Permeability with Cyclic Stretch
Int. J. Mol. Sci. 2019, 20(4), 948; https://doi.org/10.3390/ijms20040948
Received: 22 January 2019 / Revised: 11 February 2019 / Accepted: 19 February 2019 / Published: 22 February 2019
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Abstract
Mechanical ventilation can be damaging, and can cause or exacerbate ventilator-induced lung injury (VILI). The human epidermal growth factor receptor (HER) ligand neuregulin-1 (NRG1) activates HER2 heterodimerization with HER3, and has been implicated in inflammatory injuries. We hypothesized that HER2 activation contributes to [...] Read more.
Mechanical ventilation can be damaging, and can cause or exacerbate ventilator-induced lung injury (VILI). The human epidermal growth factor receptor (HER) ligand neuregulin-1 (NRG1) activates HER2 heterodimerization with HER3, and has been implicated in inflammatory injuries. We hypothesized that HER2 activation contributes to VILI. We analyzed a database of differentially expressed genes between cyclically stretched and unstretched rat alveolar epithelial cells (RAEC) for HER ligands and validated the differential expression. The effect of the ligand and HER2 inhibition on RAEC permeability was tested, and in vivo relevance was assessed in a rat model of VILI. Analysis of our expression array revealed the upregulation of NRG1 and amphiregulin (AREG) with stretch. NRG1 protein, but not AREG, increased after stretch in culture media. Treatment with an NRG1-cleavage inhibitor (TAPI2) or an inhibitor of NRG1-binding (anti-HER3 antibody) reduced HER2 phosphorylation and partially mitigated stretch-induced permeability, with the upregulation of claudin-7. The results were reproduced by treatment with a direct inhibitor of HER2 phosphorylation (AG825). The transfection of microRNA miR-15b, predicted to negatively regulate NRG1, also attenuated stretch-induced permeability, and was associated with lower NRG1 mRNA levels. In rats ventilated at damaging tidal volumes, AG825 partly attenuated VILI. We concluded that cyclic stretch activates HER2 via the HER3 ligand NRG1, leading to increased permeability. Outcomes were mitigated by the downregulation of NRG1, prevention of NRG1 binding, and most strongly by the direct inhibition of HER2. In vivo HER2 inhibition also attenuated VILI. Ligand-dependent HER2 activation is a potential target for reducing VILI. Full article
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Graphical abstract

Int. J. Mol. Sci. EISSN 1422-0067 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
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