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

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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: closed (29 October 2019) | Viewed by 43546

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Special Issue Editor

Prof. Dr. Anna K. Kurdowska

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Guest Editor

Department of Cellular and Molecular Biology, University of Texas Health Science Center, Tyler, TX 75708, USA
Interests: inflammation; pro-inflammatory cells; mediators of inflammation; innate immunity; cell signaling; signal transduction; lung disease
Special Issues, Collections and Topics in MDPI journals

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

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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. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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 (10 papers)

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Research

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18 pages, 3281 KiB

Open AccessArticle

Dietary Antioxidants Significantly Attenuate Hyperoxia-Induced Acute Inflammatory Lung Injury by Enhancing Macrophage Function via Reducing the Accumulation of Airway HMGB1

by Vivek Patel, Katelyn Dial, Jiaqi Wu, Alex G. Gauthier, Wenjun Wu, Mosi Lin, Michael G. Espey, Douglas D. Thomas, Charles R. Ashby, Jr. and Lin L. Mantell

Int. J. Mol. Sci. 2020, 21(3), 977; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21030977 - 01 Feb 2020

Cited by 46 | Viewed by 6214

Abstract

Mechanical ventilation with hyperoxia is the major supportive measure to treat patients with acute lung injury and acute respiratory distress syndrome (ARDS). However, prolonged exposure to hyperoxia can induce oxidative inflammatory lung injury. Previously, we have shown that high levels of airway high-mobility group box 1 protein (HMGB1) mediate hyperoxia-induced acute lung injury (HALI). Using both ascorbic acid (AA, also known as vitamin C) and sulforaphane (SFN), an inducer of nuclear factor (erythroid-derived 2)-like 2 (Nrf2), we tested the hypothesis that dietary antioxidants can mitigate HALI by ameliorating HMGB1-compromised macrophage function in phagocytosis by attenuating hyperoxia-induced extracellular HMGB1 accumulation. Our results indicated that SFN, which has been shown to attenute HALI in mice exposed to hyperoxia, dose-dependently restored hyperoxia-compromised macrophage function in phagocytosis (75.9 ± 3.5% in 0.33 µM SFN versus 50.7 ± 1.8% in dimethyl sulfoxide (DMSO) control, p < 0.05) by reducing oxidative stress and HMGB1 release from cultured macrophages (47.7 ± 14.7% in 0.33 µM SFN versus 93.1 ± 14.6% in DMSO control, p < 0.05). Previously, we have shown that AA enhances hyperoxic macrophage functions by reducing hyperoxia-induced HMGB1 release. Using a mouse model of HALI, we determined the effects of AA on hyperoxia-induced inflammatory lung injury. The i.p. administration of 50 mg/kg of AA to mice exposed to 72 h of ≥98% O₂ significantly decreased hyperoxia-induced oxidative and nitrosative stress in mouse lungs. There was a significant decrease in the levels of airway HMGB1 (43.3 ± 12.2% in 50 mg/kg AA versus 96.7 ± 9.39% in hyperoxic control, p < 0.05), leukocyte infiltration (60.39 ± 4.137% leukocytes numbers in 50 mg/kg AA versus 100 ± 5.82% in hyperoxic control, p < 0.05) and improved lung integrity in mice treated with AA. Our study is the first to report that the dietary antioxidants, ascorbic acid and sulforaphane, ameliorate HALI and attenuate hyperoxia-induced macrophage dysfunction through an HMGB1-mediated pathway. Thus, dietary antioxidants could be used as potential treatments for oxidative-stress-induced acute inflammatory lung injury in patients receiving mechanical ventilation. Full article

(This article belongs to the Special Issue Acute Lung Injury – New Insights into the Mechanisms and Emerging Therapies)

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14 pages, 3422 KiB

Open AccessArticle

Pre-Treatment with Ten-Minute Carbon Dioxide Inhalation Prevents Lipopolysaccharide-Induced Lung Injury in Mice via Down-Regulation of Toll-Like Receptor 4 Expression

by Shih-En Tang, Shu-Yu Wu, Shi-Jye Chu, Yuan-Sheng Tzeng, Chung-Kan Peng, Chou-Chin Lan, Wann-Cherng Perng, Chin-Pyng Wu and Kun-Lun Huang

Int. J. Mol. Sci. 2019, 20(24), 6293; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20246293 - 13 Dec 2019

Cited by 16 | Viewed by 3197

Abstract

Various animal studies have shown beneficial effects of hypercapnia in lung injury. However, in patients with acute respiratory distress syndrome (ARDS), there is controversial information regarding the effect of hypercapnia on outcomes. The duration of carbon dioxide inhalation may be the key to the protective effect of hypercapnia. We investigated the effect of pre-treatment with inhaled carbon dioxide on lipopolysaccharide (LPS)-induced lung injury in mice. C57BL/6 mice were randomly divided into a control group or an LPS group. Each LPS group received intratracheal LPS (2 mg/kg); the LPS groups were exposed to hypercapnia (5% carbon dioxide) for 10 min or 60 min before LPS. Bronchoalveolar lavage fluid (BALF) and lung tissues were collected to evaluate the degree of lung injury. LPS significantly increased the ratio of lung weight to body weight; concentrations of BALF protein, tumor necrosis factor-α, and CXCL2; protein carbonyls; neutrophil infiltration; and lung injury score. LPS induced the degradation of the inhibitor of nuclear factor-κB-α (IκB-α) and nuclear translocation of NF-κB. LPS increased the surface protein expression of toll-like receptor 4 (TLR4). Pre-treatment with inhaled carbon dioxide for 10 min, but not for 60 min, inhibited LPS-induced pulmonary edema, inflammation, oxidative stress, lung injury, and TLR4 surface expression, and, accordingly, reduced NF-κB signaling. In summary, our data demonstrated that pre-treatment with 10-min carbon dioxide inhalation can ameliorate LPS-induced lung injury. The protective effect may be associated with down-regulation of the surface expression of TLR4 in the lungs. Full article

(This article belongs to the Special Issue Acute Lung Injury – New Insights into the Mechanisms and Emerging Therapies)

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17 pages, 2240 KiB

Open AccessArticle

Adaptive Support Ventilation Attenuates Ventilator Induced Lung Injury: Human and Animal Study

by Yu-Ling Dai, Chin-Pyng Wu, Gee-Gwo Yang, Hung Chang, Chung-Kan Peng and Kun-Lun Huang

Int. J. Mol. Sci. 2019, 20(23), 5848; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20235848 - 21 Nov 2019

Cited by 10 | Viewed by 3594

Abstract

Adaptive support ventilation (ASV) is a closed-loop ventilation, which can make automatic adjustments in tidal volume (V_T) and respiratory rate based on the minimal work of breathing. The purpose of this research was to study whether ASV can provide a protective ventilation pattern to decrease the risk of ventilator-induced lung injury in patients of acute respiratory distress syndrome (ARDS). In the clinical study, 15 ARDS patients were randomly allocated to an ASV group or a pressure-control ventilation (PCV) group. There was no significant difference in the mortality rate and respiratory parameters between these two groups, suggesting the feasible use of ASV in ARDS. In animal experiments of 18 piglets, the ASV group had a lower alveolar strain compared with the volume-control ventilation (VCV) group. The ASV group exhibited less lung injury and greater alveolar fluid clearance compared with the VCV group. Tissue analysis showed lower expression of matrix metalloproteinase 9 and higher expression of claudin-4 and occludin in the ASV group than in the VCV group. In conclusion, the ASV mode is capable of providing ventilation pattern fitting into the lung-protecting strategy; this study suggests that ASV mode may effectively reduce the risk or severity of ventilator-associated lung injury in animal models. Full article

(This article belongs to the Special Issue Acute Lung Injury – New Insights into the Mechanisms and Emerging Therapies)

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13 pages, 2022 KiB

Open AccessArticle

Differential Protein Expression Profiles of Bronchoalveolar Lavage Fluid Following Lipopolysaccharide-Induced Direct and Indirect Lung Injury in Mice

by Xinping Yue and Jessie J. Guidry

Int. J. Mol. Sci. 2019, 20(14), 3401; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20143401 - 11 Jul 2019

Cited by 17 | Viewed by 5653

Abstract

The pathogenic mechanisms of acute lung injury due to direct and indirect pulmonary insults are incompletely understood. Using an unbiased, discovery and quantitative proteomic approach, we examined bronchoalveolar lavage fluid (BALF) proteome following lipopolysaccharide (LPS)-induced direct and indirect lung injury in mice. A total of 1017 proteins were both identified and quantitated in BALF from control, intratracheal (I.T., direct) and intraperitoneal (I.P., indirect) LPS-treated mice. The two LPS groups shared 13 up-regulated and 22 down-regulated proteins compared to the control group. Ingenuity pathway analysis revealed that acute-phase response signaling was activated by both I.T. and I.P. LPS; however, the magnitude of activation was much greater in the I.T. LPS group. Intriguingly, two canonical signaling pathways, liver X receptor/retinoid X receptor activation, and the production of nitric oxide and reactive oxygen species in macrophages, were activated by I.T. but suppressed by I.P. LPS. Cxcl15 (also known as lungkine) was also up-regulated by I.T. but down-regulated by I.P. LPS. In conclusion, our quantitative discovery-based proteomic approach identified commonalities, as well as significant differences in BALF protein expression profiles between LPS-induced direct and indirect lung injury, and importantly, LPS-induced indirect lung injury resulted in suppression of select components of lung innate immunity. Full article

(This article belongs to the Special Issue Acute Lung Injury – New Insights into the Mechanisms and Emerging Therapies)

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16 pages, 1275 KiB

Open AccessCommunication

A Peptide Inhibitor of NADPH Oxidase (NOX2) Activation Markedly Decreases Mouse Lung Injury and Mortality Following Administration of Lipopolysaccharide (LPS)

by Aron B. Fisher, Chandra Dodia, Shampa Chatterjee and Sheldon I. Feinstein

Int. J. Mol. Sci. 2019, 20(10), 2395; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20102395 - 15 May 2019

Cited by 21 | Viewed by 3754 | Correction

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 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

(This article belongs to the Special Issue Acute Lung Injury – New Insights into the Mechanisms and Emerging Therapies)

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13 pages, 3093 KiB

Open AccessArticle

Essential Role of Visfatin in Lipopolysaccharide and Colon Ascendens Stent Peritonitis-Induced Acute Lung Injury

by Yi-Chen Lee, Chun-Yu Lin, Yen-Hsu Chen, Wen-Chin Chiu, Yen-Yun Wang, Chin Hsu, Stephen Chu-Sung Hu, Yu-Han Su and Shyng-Shiou F. Yuan

Int. J. Mol. Sci. 2019, 20(7), 1678; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20071678 - 04 Apr 2019

Cited by 13 | Viewed by 2818

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 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

(This article belongs to the Special Issue Acute Lung Injury – New Insights into the Mechanisms and Emerging Therapies)

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11 pages, 1646 KiB

Open AccessArticle

HER2 Signaling Implicated in Regulating Alveolar Epithelial Permeability with Cyclic Stretch

by Nadir Yehya, Min Jae Song, Gladys G. Lawrence and Susan S. Margulies

Int. J. Mol. Sci. 2019, 20(4), 948; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20040948 - 22 Feb 2019

Cited by 4 | Viewed by 2677

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 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

(This article belongs to the Special Issue Acute Lung Injury – New Insights into the Mechanisms and Emerging Therapies)

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Review

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24 pages, 990 KiB

Open AccessReview

Corticosteroids in Acute Lung Injury: The Dilemma Continues

by Daniela Mokra, Pavol Mikolka, Petra Kosutova and Juraj Mokry

Int. J. Mol. Sci. 2019, 20(19), 4765; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20194765 - 25 Sep 2019

Cited by 96 | Viewed by 8346

Abstract

Acute lung injury (ALI) represents a serious heterogenous pulmonary disorder with high mortality. Despite improved understanding of the pathophysiology, the efficacy of standard therapies such as lung-protective mechanical ventilation, prone positioning and administration of neuromuscular blocking agents is limited. Recent studies have shown some benefits of corticosteroids (CS). Prolonged use of CS can shorten duration of mechanical ventilation, duration of hospitalization or improve oxygenation, probably because of a wide spectrum of potentially desired actions including anti-inflammatory, antioxidant, pulmonary vasodilator and anti-oedematous effects. However, the results from experimental vs. clinical studies as well as among the clinical trials are often controversial, probably due to differences in the designs of the trials. Thus, before the use of CS in ARDS can be definitively confirmed or refused, the additional studies should be carried on to determine the most appropriate dosing, timing and choice of CS and to analyse the potential risks of CS administration in various groups of patients with ARDS. Full article

(This article belongs to the Special Issue Acute Lung Injury – New Insights into the Mechanisms and Emerging Therapies)

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19 pages, 1616 KiB

Open AccessReview

Genomics and the Acute Respiratory Distress Syndrome: Current and Future Directions

by Tamara Hernández-Beeftink, Beatriz Guillen-Guio, Jesús Villar and Carlos Flores

Int. J. Mol. Sci. 2019, 20(16), 4004; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20164004 - 16 Aug 2019

Cited by 23 | Viewed by 5119

Abstract

The excessive hospital mortality associated with acute respiratory distress syndrome (ARDS) in adults mandates an urgent need for developing new therapies and tools for the early risk assessment of these patients. ARDS is a heterogeneous syndrome with multiple different pathogenetic processes contributing differently in different patients depending on clinical as well as genetic factors. Identifying genetic-based biomarkers holds the promise for establishing effective predictive and prognostic stratification methods and for targeting new therapies to improve ARDS outcomes. Here we provide an updated review of the available evidence supporting the presence of genetic factors that are predictive of ARDS development and of fatal outcomes in adult critically ill patients and that have been identified by applying different genomic and genetic approaches. We also introduce other incipient genomics approximations, such as admixture mapping, metagenomics and genome sequencing, among others, that will allow to boost this knowledge and likely reveal new genetic predictors of ARDS susceptibility and prognosis among critically ill patients. Full article

(This article belongs to the Special Issue Acute Lung Injury – New Insights into the Mechanisms and Emerging Therapies)

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