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Acute Lung Injury – New Insights into the Mechanisms and Emerging Therapies 2.0

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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 (20 August 2020) | Viewed by 50904

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Prof. Dr. Anna K. Kurdowska

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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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Keywords

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

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Published Papers (9 papers)

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Research

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16 pages, 6653 KiB

Open AccessArticle

Acute Hyperglycemia Aggravates Lung Injury via Activation of the SGK1–NKCC1 Pathway

by Chin-Pyng Wu, Kun-Lun Huang, Chung-Kan Peng and Chou-Chin Lan

Int. J. Mol. Sci. 2020, 21(13), 4803; https://doi.org/10.3390/ijms21134803 - 7 Jul 2020

Cited by 20 | Viewed by 3401

Abstract

Acute lung injury (ALI) is characterized by severe hypoxemia and has significantly high mortality rates. Acute hyperglycemia occurs in patients with conditions such as sepsis or trauma, among others, and it results in aggravated inflammation and induces damage in patients with ALI. Regulation of alveolar fluid is essential for the development and resolution of pulmonary edema in lung injury. Pulmonary sodium-potassium-chloride co-transporter 1 (NKCC1) regulates the net influx of ions and water into alveolar cells. The activation of with-no-lysine kinase 4 (WNK4), STE20/SPS1-related proline/alanine rich kinase (SPAK) and the NKCC1 pathway lead to an increase in the expression of NKCC1 and aggravation of ALI. Moreover, hyperglycemia is known to induce NKCC1 expression via the activation of the serum-glucocorticoid kinase 1 (SGK1)–NKCC1 pathway. We aim to evaluate the influence of acute hyperglycemia on the SGK1–NKCC1 pathway in ALI. ALI was induced using a high tidal volume for four hours in a rat model. Acute hyperglycemia was induced by injection with 0.5 mL of 40% glucose solution followed by continuous infusion at 2 mL/h. The animals were divided into sham, sham+ hyperglycemia, ALI, ALI + hyperglycemia, ALI + inhaled bumetanide (NKCC1 inhibitor) pretreatment, ALI + hyperglycemia + inhalational bumetanide pretreatment, and ALI + hyperglycemia + post-ALI inhalational bumetanide groups. Severe lung injury along with pulmonary edema, alveolar protein leakage, and lung inflammation was observed in ALI with hyperglycemia than in ALI without hyperglycemia. This was concurrent with the higher expression of pro-inflammatory cytokines, infiltration of neutrophils and alveolar macrophages (AM) 1, and NKCC1 expression. Inhalational NKCC1 inhibitor significantly inhibited the SGK1–NKCC1, and WNK4–SPAK–NKCC1 pathways. Additionally, it reduced pulmonary edema, inflammation, levels of pro-inflammatory cytokines, neutrophils and AM1 and increased AM2. Therefore, acute hyperglycemia aggravates lung injury via the further activation of the SGK1–NKCC1 pathway. The NKCC1 inhibitor can effectively attenuate lung injury aggravated by acute hyperglycemia. Full article

(This article belongs to the Special Issue Acute Lung Injury – New Insights into the Mechanisms and Emerging Therapies 2.0)

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19 pages, 5458 KiB

Open AccessArticle

The HSP90 Inhibitor, AUY-922, Ameliorates the Development of Nitrogen Mustard-Induced Pulmonary Fibrosis and Lung Dysfunction in Mice

by Pavel Solopov, Ruben M. L. Colunga Biancatelli, Margarita Marinova, Christiana Dimitropoulou and John D. Catravas

Int. J. Mol. Sci. 2020, 21(13), 4740; https://doi.org/10.3390/ijms21134740 - 3 Jul 2020

Cited by 24 | Viewed by 4174

Abstract

Increased levels of heat shock protein 90 (HSP90) have been recently implicated in the pathogenesis of pulmonary fibrosis and the use of HSP90 inhibitors constitutes a potential therapeutic approach. Similarly, acute exposure to nitrogen mustard (NM) is related to the development of chronic lung injury driven by TNF-α, TGF-β, ERK and HSP90. Thus, we developed a murine model of NM-induced pulmonary fibrosis by instilling C57BI/6J mice with 0.625 mg/kg mechlorethamine hydrochloride. After 24 h, mice began receiving AUY-922, a second generation HSP90 inhibitor, at 1 mg/kg 2 times per week or 2 mg/kg 3 times per week, for either 10 or 30 days. AUY-922 suppressed the NM-induced sustained inflammation, as reflected in the reduction of leukocyte and protein concentrations in bronchoalveolar lavage fluid (BALF), and inhibited the activation of pro-fibrotic biomarkers, ERK and HSP90. Furthermore, AUY-922 maintained normal lung function, decreased the overexpression and accumulation of extracellular matrix proteins, and dramatically reduced histologic evidence of fibrosis in the lungs of mice exposed to NM. The HSP90 inhibitor, AUY-922, successfully blocked the adverse effects associated with acute exposures to NM, representing a promising approach against NM-induced pulmonary fibrosis. Full article

(This article belongs to the Special Issue Acute Lung Injury – New Insights into the Mechanisms and Emerging Therapies 2.0)

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17 pages, 2709 KiB

Open AccessArticle

Effects of PDE3 Inhibitor Olprinone on the Respiratory Parameters, Inflammation, and Apoptosis in an Experimental Model of Acute Respiratory Distress Syndrome

by Petra Kosutova, Pavol Mikolka, Sona Balentova, Marian Adamkov, Andrea Calkovska and Daniela Mokra

Int. J. Mol. Sci. 2020, 21(9), 3382; https://doi.org/10.3390/ijms21093382 - 11 May 2020

Cited by 9 | Viewed by 3223

Abstract

This study aimed to investigate whether a selective phosphodiesterase-3 (PDE3) inhibitor olprinone can positively influence the inflammation, apoptosis, and respiratory parameters in animals with acute respiratory distress syndrome (ARDS) model induced by repetitive saline lung lavage. Adult rabbits were divided into 3 groups: ARDS without therapy (ARDS), ARDS treated with olprinone i.v. (1 mg/kg; ARDS/PDE3), and healthy ventilated controls (Control), and were oxygen-ventilated for the following 4 h. Dynamic lung–thorax compliance (Cdyn), mean airway pressure (MAP), arterial oxygen saturation (SaO₂), alveolar-arterial gradient (AAG), ratio between partial pressure of oxygen in arterial blood to a fraction of inspired oxygen (PaO₂/FiO₂), oxygenation index (OI), and ventilation efficiency index (VEI) were evaluated every hour. Post mortem, inflammatory and oxidative markers (interleukin (IL)-6, IL-1β, a receptor for advanced glycation end products (RAGE), IL-10, total antioxidant capacity (TAC), 3-nitrotyrosine (3NT), and malondialdehyde (MDA) and apoptosis (apoptotic index and caspase-3) were assessed in the lung tissue. Treatment with olprinone reduced the release of inflammatory mediators and markers of oxidative damage decreased apoptosis of epithelial cells and improved respiratory parameters. The results indicate a future potential of PDE3 inhibitors also in the therapy of ARDS. Full article

(This article belongs to the Special Issue Acute Lung Injury – New Insights into the Mechanisms and Emerging Therapies 2.0)

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17 pages, 14251 KiB

Open AccessArticle

Forefront: MiR-34a-Knockout Mice with Wild Type Hematopoietic Cells, Retain Persistent Fibrosis Following Lung Injury

by Raanan Bulvik, Moshe Biton, Neville Berkman, Raphael Breuer and Shulamit B. Wallach-Dayan

Int. J. Mol. Sci. 2020, 21(6), 2228; https://doi.org/10.3390/ijms21062228 - 23 Mar 2020

Cited by 9 | Viewed by 2806

Abstract

MicroRNAs (miRs) are known to limit gene expression at the post-transcriptional level and have important roles in the pathogenesis of various conditions, including acute lung injury (ALI) and fibrotic diseases such as idiopathic pulmonary fibrosis (IPF). In this study, we found increased levels of miR-34 at times of fibrosis resolution following injury, in myofibroblasts from Bleomycin-treated mouse lungs, which correlates with susceptibility to cell death induced by immune cells. On the contrary, a substantial downregulation of miR-34 was detected at stages of evolution, when fibroblasts resist cell death. Concomitantly, we found an inverse correlation between miR-34 levels with that of the survival molecule FLICE-like inhibitory protein (FLIP) in lung myofibroblasts from humans with IPF and the experimental model. Forced upregulation of miR-34 with miR-34 mimic in human IPF fibrotic-lung myofibroblasts led to decreased cell survival through downregulation of FLIP. Using chimeric miR-34 knock-out (KO)-C57BL/6 mice with miR34KO myofibroblasts but wild-type (WT) hematopoietic cells, we found, in contrast to WT mice, increased and persistent FLIP levels with a more severe fibrosis and with no signs of resolution as detected in pathology and collagen accumulation. Moreover, a mimic of miR-34a decreased FLIP expression and susceptibility to cell death was regained in miR-34KO fibroblasts. Through this study, we show for the first time an inverse correlation between miR-34a and FLIP expression in myofibroblasts, which affects survival, and accumulation in lung fibrosis. Reprogramming fibrotic-lung myofibroblasts to regain susceptibility to cell-death by specifically increasing their miR34a and downregulating FLIP, may be a useful strategy, enabling tissue regeneration following lung injury. Full article

(This article belongs to the Special Issue Acute Lung Injury – New Insights into the Mechanisms and Emerging Therapies 2.0)

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Review

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20 pages, 1406 KiB

Open AccessReview

PPAR Gamma: From Definition to Molecular Targets and Therapy of Lung Diseases

by Márcia V. de Carvalho, Cassiano F. Gonçalves-de-Albuquerque and Adriana R. Silva

Int. J. Mol. Sci. 2021, 22(2), 805; https://doi.org/10.3390/ijms22020805 - 15 Jan 2021

Cited by 59 | Viewed by 10161

Abstract

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily that regulate the expression of genes related to lipid and glucose metabolism and inflammation. There are three members: PPARα, PPARβ or PPARγ. PPARγ have several ligands. The natural agonists are omega 9, curcumin, eicosanoids and others. Among the synthetic ligands, we highlight the thiazolidinediones, clinically used as an antidiabetic. Many of these studies involve natural or synthetic products in different pathologies. The mechanisms that regulate PPARγ involve post-translational modifications, such as phosphorylation, sumoylation and ubiquitination, among others. It is known that anti-inflammatory mechanisms involve the inhibition of other transcription factors, such as nuclear factor kB(NFκB), signal transducer and activator of transcription (STAT) or activator protein 1 (AP-1), or intracellular signaling proteins such as mitogen-activated protein (MAP) kinases. PPARγ transrepresses other transcription factors and consequently inhibits gene expression of inflammatory mediators, known as biomarkers for morbidity and mortality, leading to control of the exacerbated inflammation that occurs, for instance, in lung injury/acute respiratory distress. Many studies have shown the therapeutic potentials of PPARγ on pulmonary diseases. Herein, we describe activities of the PPARγ as a modulator of inflammation, focusing on lung injury and including definition and mechanisms of regulation, biological effects and molecular targets, and its role in lung diseases caused by inflammatory stimuli, bacteria and virus, and molecular-based therapy. Full article

(This article belongs to the Special Issue Acute Lung Injury – New Insights into the Mechanisms and Emerging Therapies 2.0)

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16 pages, 840 KiB

Open AccessReview

Novel Perspectives Regarding the Pathology, Inflammation, and Biomarkers of Acute Respiratory Distress Syndrome

by Pradeesh Sivapalan, Barbara Bonnesen and Jens-Ulrik Jensen

Int. J. Mol. Sci. 2021, 22(1), 205; https://doi.org/10.3390/ijms22010205 - 28 Dec 2020

Cited by 7 | Viewed by 5521

Abstract

Acute respiratory distress syndrome (ARDS) is an acute inflammation of the lung resulting from damage to the alveolar–capillary membrane, and it is diagnosed using a combination of clinical and physiological variables. ARDS develops in approximately 10% of hospitalised patients with pneumonia and has a mortality rate of approximately 40%. Recent research has identified several biomarkers associated with ARDS pathophysiology, and these may be useful for diagnosing and monitoring ARDS. They may also highlight potential therapeutic targets. This review summarises our current understanding of those clinical biomarkers: (1) biomarkers of alveolar and bronchiolar injury, (2) biomarkers of endothelial damage and coagulation, and (3) biomarkers for treatment responses. Full article

(This article belongs to the Special Issue Acute Lung Injury – New Insights into the Mechanisms and Emerging Therapies 2.0)

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31 pages, 1252 KiB

Open AccessReview

Endothelial Damage in Acute Respiratory Distress Syndrome

by Alice G. Vassiliou, Anastasia Kotanidou, Ioanna Dimopoulou and Stylianos E. Orfanos

Int. J. Mol. Sci. 2020, 21(22), 8793; https://doi.org/10.3390/ijms21228793 - 20 Nov 2020

Cited by 133 | Viewed by 10800

Abstract

The pulmonary endothelium is a metabolically active continuous monolayer of squamous endothelial cells that internally lines blood vessels and mediates key processes involved in lung homoeostasis. Many of these processes are disrupted in acute respiratory distress syndrome (ARDS), which is marked among others by diffuse endothelial injury, intense activation of the coagulation system and increased capillary permeability. Most commonly occurring in the setting of sepsis, ARDS is a devastating illness, associated with increased morbidity and mortality and no effective pharmacological treatment. Endothelial cell damage has an important role in the pathogenesis of ARDS and several biomarkers of endothelial damage have been tested in determining prognosis. By further understanding the endothelial pathobiology, development of endothelial-specific therapeutics might arise. In this review, we will discuss the underlying pathology of endothelial dysfunction leading to ARDS and emerging therapies. Furthermore, we will present a brief overview demonstrating that endotheliopathy is an important feature of hospitalised patients with coronavirus disease-19 (COVID-19). Full article

(This article belongs to the Special Issue Acute Lung Injury – New Insights into the Mechanisms and Emerging Therapies 2.0)

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14 pages, 1827 KiB

Open AccessReview

Isolated Lung Perfusion in the Management of Acute Respiratory Distress Syndrome

by Nathan Haywood, Matthew R. Byler, Aimee Zhang, Mark E. Roeser, Irving L. Kron and Victor E. Laubach

Int. J. Mol. Sci. 2020, 21(18), 6820; https://doi.org/10.3390/ijms21186820 - 17 Sep 2020

Cited by 3 | Viewed by 3280

Abstract

Acute respiratory distress syndrome (ARDS) is associated with high morbidity and mortality, and current management has a dramatic impact on healthcare resource utilization. While our understanding of this disease has improved, the majority of treatment strategies remain supportive in nature and are associated with continued poor outcomes. There is a dramatic need for the development and breakthrough of new methods for the treatment of ARDS. Isolated machine lung perfusion is a promising surgical platform that has been associated with the rehabilitation of injured lungs and the induction of molecular and cellular changes in the lung, including upregulation of anti-inflammatory and regenerative pathways. Initially implemented in an ex vivo fashion to evaluate marginal donor lungs prior to transplantation, recent investigations of isolated lung perfusion have shifted in vivo and are focused on the management of ARDS. This review presents current tenants of ARDS management and isolated lung perfusion, with a focus on how ex vivo lung perfusion (EVLP) has paved the way for current investigations utilizing in vivo lung perfusion (IVLP) in the treatment of severe ARDS. Full article

(This article belongs to the Special Issue Acute Lung Injury – New Insights into the Mechanisms and Emerging Therapies 2.0)

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17 pages, 1466 KiB

Open AccessReview

Pseudomonas Aeruginosa Induced Cell Death in Acute Lung Injury and Acute Respiratory Distress Syndrome

by Rushikesh Deshpande and Chunbin Zou

Int. J. Mol. Sci. 2020, 21(15), 5356; https://doi.org/10.3390/ijms21155356 - 28 Jul 2020

Cited by 52 | Viewed by 6536

Abstract

Pseudomonas aeruginosa is an important opportunistic pathogen responsible for the cause of acute lung injury and acute respiratory distress syndrome. P. aeruginosa isthe leading species isolated from patients with nosocomial infection and is detected in almost all the patients with long term ventilation in critical care units. P. aeruginosa infection is also the leading cause of deleterious chronic lung infections in patients suffering from cystic fibrosis as well as the major reason for morbidity in people with chronic obstructive pulmonary disease. P. aeruginosa infections are linked to diseases with high mortality rates and are challenging for treatment, for which no effective remedies have been developed. Massive lung epithelial cell death is a hallmark of severe acute lung injury and acute respiratory distress syndrome caused by P. aeruginosa infection. Lung epithelial cell death poses serious challenges to air barrier and structural integrity that may lead to edema, cytokine secretion, inflammatory infiltration, and hypoxia. Here we review different types of cell death caused by P. aeruginosa serving as a starting point for the diseases it is responsible for causing. We also review the different mechanisms of cell death and potential therapeutics in countering the serious challenges presented by this deadly bacterium. Full article

(This article belongs to the Special Issue Acute Lung Injury – New Insights into the Mechanisms and Emerging Therapies 2.0)

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