Acute respiratory distress syndrome readmissions: A nationwide cross-sectional analysis of epidemiology and costs of care.

BACKGROUND: Acute Respiratory Distress Syndrome affects approximately 10% of patients admitted to intensive care units internationally, with as many as 40%-52% of patients reporting re-hospitalization within one year. RESEARCH QUESTION/AIM: To describe the epidemiology of patients with acute respiratory distress syndrome who require 30-day readmission, and to describe associated costs. STUDY DESIGN AND METHODS: A cross-sectional analysis of the 2016 Healthcare Cost and Utilization Project's Nationwide Readmission Database, which is a population-based administrative database which includes discharge data from U.S. hospitals. Inclusion criteria: hospital discharge records for adults age > 17 years old, with a diagnosis of ARDS on index admission, with associated procedure codes for endotracheal intubation and/or invasive mechanical ventilation, who were discharged alive. Primary exposure is adult hospitalization for meeting criteria as described. The primary outcome measure is 30-day readmission rate, as well as patient characteristics and time distribution of readmissions. RESULTS: Nationally, 25,170 admissions meeting criteria were identified. Index admission mortality rate was 37.5% (95% confidence interval [CI], 36.2-38.8). 15,730 records of those surviving hospitalization had complete discharge information. 30-day readmission rate was 18.4%, with 14% of total readmissions occurring within 2 calendar days of discharge; these early readmissions had higher mortality risk (odds ratio 1.82, 95% CI 1.05-6.56) compared with readmission in subsequent days. For the closest all-cause readmission within 30 days, the mean cost was $26,971, with a total national cost of over $75.6 million. INTERPRETATION: Thirty-day readmission occurred in 18.4% of patients with acute respiratory distress syndrome in this sample, and early readmission is strongly associated with increased mortality compared to late readmission. Further research is needed to clarify whether the rehospitalizations or associated mortalities are preventable.

Targeting MMP-Regulation of Inflammation to Increase Metabolic Tolerance to COVID-19 Pathologies: A Hypothesis.

Many individuals infected with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) develop no or only mild symptoms, but some can go on onto develop a spectrum of pathologies including pneumonia, acute respiratory distress syndrome, respiratory failure, systemic inflammation, and multiorgan failure. Many pathogens, viral and non-viral, can elicit these pathologies, which justifies reconsidering whether the target of therapeutic approaches to fight pathogen infections should be (a) the pathogen itself, (b) the pathologies elicited by the pathogen interaction with the human host, or (c) a combination of both. While little is known about the immunopathology of SARS-CoV-2, it is well-established that the above-mentioned pathologies are associated with hyper-inflammation, tissue damage, and the perturbation of target organ metabolism. Mounting evidence has shown that these processes are regulated by endoproteinases (particularly, matrix metalloproteinases (MMPs)). Here, we review what is known about the roles played by MMPs in the development of COVID-19 and postulate a mechanism by which MMPs could influence energy metabolism in target organs, such as the lung. Finally, we discuss the suitability of MMPs as therapeutic targets to increase the metabolic tolerance of the host to damage inflicted by the pathogen infection, with a focus on SARS-CoV-2.

α1-Antitrypsin: Key Player or Bystander in Acute Respiratory Distress Syndrome?

Acute respiratory distress syndrome is characterized by hypoxemia, altered alveolar-capillary permeability, and neutrophil-dominated inflammatory pulmonary edema. Despite decades of research, an effective drug therapy for acute respiratory distress syndrome remains elusive. The ideal pharmacotherapy for acute respiratory distress syndrome should demonstrate antiprotease activity and target injurious inflammatory pathways while maintaining host defense against infection. Furthermore, a drug with a reputable safety profile, low possibility of off-target effects, and well-known pharmacokinetics would be desirable. The endogenous 52-kd serine protease α1-antitrypsin has the potential to be a novel treatment option for acute respiratory distress syndrome. The main function of α1-antitrypsin is as an antiprotease, targeting neutrophil elastase in particular. However, studies have also highlighted the role of α1-antitrypsin in the modulation of inflammation and bacterial clearance. In light of the current SARS-CoV-2 pandemic, the identification of a treatment for acute respiratory distress syndrome is even more pertinent, and α1-antitrypsin has been implicated in the inflammatory response to SARS-CoV-2 infection.

Silent information regulator type-1 mediates amelioration of inflammatory response and oxidative stress in lipopolysaccharide-induced acute respiratory distress syndrome.

Silent information regulator type-1 (SIRT1) is crucial during the development of acute respiratory distress syndrome (ARDS). We aimed to explore whether SIRT1 activation could protect against ARDS. SIRT1 was activated by its agonist SRT1720. ARDS was induced by intraperitoneal injection of 5 mg/kg lipopolysaccharide (LPS). Lung injuries were determined by the lung wet/dry ratio, inflammatory cells in the broncho-alveolar lavage fluid (BALF) and histological analysis. Inflammatory cytokine release was detected by enzyme-linked immunosorbent assay. The accumulation of neutrophils was detected by myeloperoxidase activity. Oxidative stress was evaluated by malondialdehyde, reduced glutathione, superoxide dismutase and catalase activities. The protein expression levels were detected using western blot. SIRT1 activation, either by SRT1720 administration or recombinant SIRT1, expression eliminated high-dose LPS-induced mortality in mice, attenuated lung injury, influenced cytokine release in BALF and decreased oxidative stress in the lung tissues of ARDS mice. Mechanically, SRT1720 administration inhibited p65 phosphorylation in the lung tissues of ARDS mice. SIRT1 ameliorates inflammatory response and oxidative stress in LPS-induced ARDS.

HMGB1 suppress the expression of IL-35 by regulating Naïve CD4+ T cell differentiation and aggravating Caspase-11-dependent pyroptosis in acute lung injury.

OBJECTIVES: Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is a severe form of inflammatory lung disease. Its development and progression are regulated by cytokines. The purpose of this study was to determine the effects of HMGB1 involved in the regulation of Treg cells and IL-35. METHODS: A cecal ligation and puncture (CLP)-induced ALI model was used to investigate the changes in IL-35, Tregs, and the expression of RAGE and caspase-11 after HMGB1 inhibition (glycyrrhizin was used as an inhibitor of HMGB1). CD4+ naïve T cells sorted from C57BL/6 mice spleens were cultured to explore the role of HMGB1 in the differentiation from CD4+ naïve T cells to Tregs. RESULTS: HMGB1 promoted lung injury and uncontrolled inflammation in the CLP mouse model. HMGB1, NF-κB p65, RAGE, and caspase-11 expression in the lungs of CLP mice decreased significantly after pretreatment with glycyrrhizin. We found that the Treg proportion and IL-35 expression were upregulated in the serum and lung of CLP mice after inhibiting HMGB1. In our in vitro experiments, we found that recombinant HMGB1 significantly suppressed the proportion of CD4+CD25+FOXP3+Tregs differentiated from CD4+ naïve T cells. CONCLUSIONS: The inhibition of HMGB1 increased the proportion of Treg and expression of IL-35 and alleviated lung injury in the CLP-induced ALI model. Furthermore, inhibition of HMGB1 reduced caspase-11-dependent pyroptosis in the lungs of the CLP-induced ALI model.

The role of cytochrome P450 (CYP) enzymes in hyperoxic lung injury.

INTRODUCTION: Hyperoxic lung injury is a condition that can occur in patients in need of supplemental oxygen, such as premature infants with bronchopulmonary dysplasia or adults with acute respiratory distress syndrome. Cytochrome P450 (CYP) enzymes play critical roles in the metabolism of endogenous and exogenous compounds. AREAS COVERED: Through their complex pathways, some subfamilies of these enzymes may contribute to or protect against hyperoxic lung injury. Oxidative stress from reactive oxygen species (ROS) production is most likely a major contributor of hyperoxic lung injury. CYP1A enzymes have been shown to protect against hyperoxic lung injury while CYP1B enzymes seem to contribute to it. CYP2J2 enzymes help protect against hyperoxic lung injury by triggering EET production, thereby, increasing antioxidant enzymes. The metabolism of arachidonic acid to ω-terminal hydroxyeicosatetraenoic acid (20-HETEs) by CYP4A and CYP4F enzymes could impact hyperoxic lung injury via the vasodilating effects of 20-HETE. CYP2E1 and CYP2A enzymes may contribute to the oxidative stress in the lungs caused by ethanol- and nicotine-metabolism, respectively. EXPERT OPINION: Overall, the CYP enzymes, depending upon the isoform, play a contributory or protective role in hyperoxic lung injury, and are, therefore, ideal candidates for developing drugs that can treat oxygen-mediated lung injury.

Significance of nuclear LOXL2 inhibition in fibroblasts and myofibroblasts in the fibrotic process of acute respiratory distress syndrome.

Fibrotic scarring is an important prognostic factor of acute respiratory distress syndrome (ARDS). There are currently no antifibrotic drugs or other therapeutic agents for ARDS. Lysyl oxidase-like 2 (LOXL2), an amine oxidase, contributes to fibrotic scarring by facilitating collagen cross-linking. Recent clinical trials revealed that a monoclonal inhibitory antibody against LOXL2 failed to show benefit over placebo in patients with fibrotic disorders involving the lungs. These clinical results raise the possibility that targeting the extracellular enzymic activity of LOXL2 is not in itself sufficient to prevent fibrotic scarring. We investigated the role of LOXL2 in the pathogenesis of ARDS in vivo, in vitro, and in samples from patients with ARDS. After lung injury, LOXL2 was unevenly expressed in the nuclei of lung fibroblasts and myofibroblasts in the fibrotic phase. Nuclear LOXL2 expression was upregulated in lung fibroblasts after transforming growth factor-beta1 (TGF-ß1)-treatment. LOXL2 silencing abrogated the TGF-ß1-induced expression of a myofibrogenic-progenitor marker, the appearance of proto-myofibroblasts, and the evolution of differentiated myofibroblasts in lung fibroblasts. Nuclear upregulation of Snail was evident in myofibroblasts during the fibrotic phase after lung injury. We detected high levels of LOXL2 protein in the lungs of ARDS patients, specifically during the proliferative and fibrotic phases. Our results highlight nuclear LOXL2 in fibroblasts as a primary causative driver of cell-fate decision toward myofibroblasts and of the progression of fibrotic scarring. A nuclear-LOXL2-targeted agent could be a promising therapeutic strategy against fibrotic disorders including ARDS.

Cathepsin L in COVID-19: From Pharmacological Evidences to Genetics.

The coronavirus disease 2019 (COVID-19) pandemics is a challenge without precedent for the modern science. Acute Respiratory Discomfort Syndrome (ARDS) is the most common immunopathological event in SARS-CoV-2, SARS-CoV, and MERS-CoV infections. Fast lung deterioration results of cytokine storm determined by a robust immunological response leading to ARDS and multiple organ failure. Here, we show cysteine protease Cathepsin L (CatL) involvement with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and COVID-19 from different points of view. CatL is a lysosomal enzyme that participates in numerous physiological processes, including apoptosis, antigen processing, and extracellular matrix remodeling. CatL is implicated in pathological conditions like invasion and metastasis of tumors, inflammatory status, atherosclerosis, renal disease, diabetes, bone diseases, viral infection, and other diseases. CatL expression is up-regulated during chronic inflammation and is involved in degrading extracellular matrix, an important process for SARS-CoV-2 to enter host cells. In addition, CatL is probably involved in processing SARS-CoV-2 spike protein. As its inhibition is detrimental to SARS-CoV-2 infection and possibly exit from cells during late stages of infection, CatL could have been considered a valuable therapeutic target. Therefore, we describe here some drugs already in the market with potential CatL inhibiting capacity that could be used to treat COVID-19 patients. In addition, we discuss the possible role of host genetics in the etiology and spreading of the disease.

Exuberant fibroblast activity compromises lung function via ADAMTS4.

Severe respiratory infections can result in acute respiratory distress syndrome (ARDS)1. There are no effective pharmacological therapies that have been shown to improve outcomes for patients with ARDS. Although the host inflammatory response limits spread of and eventually clears the pathogen, immunopathology is a major contributor to tissue damage and ARDS1,2. Here we demonstrate that respiratory viral infection induces distinct fibroblast activation states, which we term extracellular matrix (ECM)-synthesizing, damage-responsive and interferon-responsive states. We provide evidence that excess activity of damage-responsive lung fibroblasts drives lethal immunopathology during severe influenza virus infection. By producing ECM-remodelling enzymes-in particular the ECM protease ADAMTS4-and inflammatory cytokines, damage-responsive fibroblasts modify the lung microenvironment to promote robust immune cell infiltration at the expense of lung function. In three cohorts of human participants, the levels of ADAMTS4 in the lower respiratory tract were associated with the severity of infection with seasonal or avian influenza virus. A therapeutic agent that targets the ECM protease activity of damage-responsive lung fibroblasts could provide a promising approach to preserving lung function and improving clinical outcomes following severe respiratory infections.

Lung Protection by Cathepsin C Inhibition: A New Hope for COVID-19 and ARDS?

Cathepsin C (CatC) is a cysteine dipeptidyl aminopeptidase that activates most of tissue-degrading elastase-related serine proteases. Thus, CatC appears as a potential therapeutic target to impair protease-driven tissue degradation in chronic inflammatory and autoimmune diseases. A depletion of proinflammatory elastase-related proteases in neutrophils is observed in patients with CatC deficiency (Papillon-Lefèvre syndrome). To address and counterbalance unwanted effects of elastase-related proteases, chemical inhibitors of CatC are being evaluated in preclinical and clinical trials. Neutrophils may contribute to the diffuse alveolar inflammation seen in acute respiratory distress syndrome (ARDS) which is currently a growing challenge for intensive care units due to the outbreak of the COVID-19 pandemic. Elimination of elastase-related neutrophil proteases may reduce the progression of lung injury in these patients. Pharmacological CatC inhibition could be a potential therapeutic strategy to prevent the irreversible pulmonary failure threatening the life of COVID-19 patients.

S-allylmercaptocysteine inhibits mucin overexpression and inflammation via MAPKs and PI3K-Akt signaling pathways in acute respiratory distress syndrome.

Cytokine storm is an important cause of acute respiratory distress syndrome and multiple organ failure. Excessive secretion and accumulation of mucins on the surface of airway cause airway obstruction and exacerbate lung infections. MUC5AC and MUC5B are the main secreted mucins and overexpressed in various inflammatory responses. S-allylmercaptocysteine, a water-soluble organic sulfur compound extracted from garlic, has anti-inflammatory and anti-oxidative effects for various pulmonary diseases. The aim of this work was to investigate the therapeutic effects of SAMC on mucin overproduction and inflammation in 16HBE cells and LPS-induced ARDS mice. Results show that SAMC treatment ameliorated inflammatory cell infiltration and lung histopathological changes in the LPS-induced ARDS mice. SAMC also inhibited the expressions of MUC5AC and MUC5B, decreased the production of pro-inflammatory markers (IL-6, TNF-α, CD86 and IL-12) and increased the production of anti-inflammatory markers (IL-10, CD206 and TGF-ß). These results confirm that SAMC had potential beneficial effects on suppressed hyperinflammation and mucin overexpression. Furthermore, SAMC exerted the therapeutic effects through the inhibition of phosphorylation of MAPKs and PI3K-Akt signaling pathways in the 16HBE cells and mice. Overall, our results demonstrate the effects of SAMC on the LPS-induced mucin overproduction and inflammation both in the 16HBE cells and mice.

Patients with acute respiratory distress syndrome exhibit increased stromelysin1 activity in the blood samples.

Enzyme activity analyses in the blood are expected to be reliable, non-invasive diagnostic as well as prognostic markers to reflect disease progression in acute lung injury (ALI). The objective of the current study was to evaluate the enzymatic activity of stromelysin1 (matrix metalloprotease-3) in the plasma/serum samples collected from ALI patients compared to the samples collected from healthy controls. Gene expression omnibus (GEO) database analysis indicated a correlation between increased stromelysin1 gene expression and the incidence of ALI in various animal models. Our analysis of patient plasma/serum samples from healthy controls and ALI patients revealed a significant, 3-fold increase in stromelysin1 activity in ALI plasma/serum compared to healthy subjects with no difference in stromelysin1 activity between the serum and plasma samples. Interestingly, no significant difference in stromelysin1 activity between non-smoking and smoking subjects was observed. These findings provide fundamental information on the potential reliability of stromelysin1 activity analysis, combined with other biomarkers in development, in blood samples for the early detection of ALI.

The Angiopoietin-Tie2 Pathway in Critical Illness.

Lethal features of sepsis and acute respiratory distress syndrome (ARDS) relate to the health of small blood vessels. For example, alveolar infiltration with proteinaceous fluid is often driven by breach of the microvascular barrier. Spontaneous thrombus formation within inflamed microvessels exacerbates organ ischemia, and in its final stages, erupts into overt disseminated intravascular coagulation. Disruption of an endothelial signaling axis, the Angiopoietin-Tie2 pathway, may mediate the abrupt transition from microvascular integrity to pathologic disruption. This review summarizes preclinical and clinical results that implicate the Tie2 pathway as a promising target to restore microvascular health in sepsis and ARDS.

Expression of sphingosine kinase 1 and sphingosine 1-phosphate receptor 3 in malaria-associated acute lung injury/acute respiratory distress syndrome in a mouse model.

This study aimed to investigate the expression of sphingosine kinase 1 (SphK-1) and sphingosine 1-phosphate receptor 3 (S1PR-3) in a mouse model of malaria-associated acute lung injury/acute respiratory distress syndrome (ALI/ARDS). DBA/2 mice were infected with Plasmodium berghei ANKA to generate an experimental model of malaria-associated ALI/ARDS. The infected mice were divided into 2 groups based on the histopathological study of lung tissues: those with and those without ALI/ARDS. The expression of the SphK-1 and S1PR-3 proteins in the lung tissues was investigated using immunohistochemical staining and Western blot analysis. In addition, the S1P level was quantified in plasma and lung tissues using an enzyme-linked immunosorbent assay (ELISA). The results demonstrated that the cellular expression of the SphK-1 and S1PR-3 proteins was significantly upregulated in endothelial cells, alveolar epithelial cells and alveolar macrophages in the lung tissues of malaria-infected mice with ALI/ARDS compared with those in the control groups. The increased expression of the SphK-1 and S1PR-3 proteins was confirmed using Western blot analysis. The concentration of S1P in plasma and lung tissues was significantly decreased in malaria-infected mice with ALI/ARDS compared with non-ALI/ARDS and control mice. Furthermore, increased expression of the SphK-1 and S1PR-3 proteins significantly correlated with lung injury scores and S1P concentrations in malaria-infected mice with ALI/ARDS. These findings highlight increased expression of SphK-1 and S1PR-3 in the lung tissues of malaria-infected mice with ALI/ARDS.

Proteasome dysfunction in alveolar type 2 epithelial cells is associated with acute respiratory distress syndrome.

Proteasomes are a critical component of quality control that regulate turnover of short-lived, unfolded, and misfolded proteins. Proteasome activity has been therapeutically targeted and considered as a treatment option for several chronic lung disorders including pulmonary fibrosis. Although pharmacologic inhibition of proteasome activity effectively prevents the transformation of fibroblasts to myofibroblasts, the effect on alveolar type 2 (AT2) epithelial cells is not clear. To address this knowledge gap, we generated a genetic model in which a proteasome subunit, RPT3, which promotes assembly of active 26S proteasome, was conditionally deleted in AT2 cells of mice. Partial deletion of RPT3 resulted in 26S proteasome dysfunction, leading to augmented cell stress and cell death. Acute loss of AT2 cells resulted in depletion of alveolar surfactant, disruption of the alveolar epithelial barrier and, ultimately, lethal acute respiratory distress syndrome (ARDS). This study underscores importance of proteasome function in maintenance of AT2 cell homeostasis and supports the need to further investigate the role of proteasome dysfunction in ARDS pathogenesis.

Role of angiotensin-converting enzyme as prognostic marker in thoracic trauma: A prospective observational study.

BACKGROUND: Chest injuries, accounting for 25% of all trauma-related deaths, are one of the main causes of death in young adults. Our priority is the early identification of life-threatening injuries both immediate and delayed. The role of various biomarkers, such as Clara cell protein 16, von Willebrand factor, interleukin-6, tumor necrosis factor, and angiopoietin, has been studied in trauma-related acute respiratory distress syndrome (ARDS). Serum angiotensin-converting enzyme (ACE) levels have been studied in non-trauma-related ARDS. The aim of this prospective observational study was to evaluate the role of ACE levels as a prognostic marker in thoracic trauma. METHODS: A prospective observational study was conducted to evaluate serum ACE levels in thoracic trauma patients and to explore its prognostic potential with regard to clinical outcome. A total of 48 thoracic trauma patients were included in the study. RESULTS: The mean ACE level in the study population was 66.54+-11.18. A strong positive correlation was found among serum ACE levels and Thoracic Trauma Severity Score (TTSS). CONCLUSION: Our study demonstrates that serum ACE levels are increased in thoracic trauma patients with higher levels, indicating the severe nature of trauma in concordance with increased TTSS scores.

Ubiquitin-proteasome signaling in lung injury.

Cell homeostasis requires precise coordination of cellular proteins function. Ubiquitination is a post-translational modification that modulates protein half-life and function and is tightly regulated by ubiquitin E3 ligases and deubiquitinating enzymes. Lung injury can progress to acute respiratory distress syndrome that is characterized by an inflammatory response and disruption of the alveolocapillary barrier resulting in alveolar edema accumulation and hypoxemia. Ubiquitination plays an important role in the pathobiology of acute lung injury as it regulates the proteins modulating the alveolocapillary barrier and the inflammatory response. Better understanding of the signaling pathways regulated by ubiquitination may lead to novel therapeutic approaches by targeting specific elements of the ubiquitination pathways.

In silico investigation of the molecular effects caused by R123H variant in secretory phospholipase A2-IIA associated with ARDS.

Phospholipase A2-IIA catalyzes the hydrolysis of the sn-2 ester of glycerophospholipids. A rare c.428G > A (p.Arg143His) variant in PLA2G2A gene was found in two infants affected by acute respiratory distress syndrome (ARDS) by whole coding region and exon/intron boundaries sequencing. To obtain insights into the possible molecular effects of the rare R123H mutation in secretory PLA2-IIA (sPLA2-IIA), molecular modelling, molecular dynamics (MD) using principal component analysis (PCA) and continuum electrostatic calculations were conducted on the crystal structure of the wild type protein and on a generated model structure of the R123H mutant. Analysis of MD trajectories indicate that the overall stability of the protein is not affected by this mutation but nevertheless the catalytically crucial H-bond between Tyr51 and Asp91 as well as main electrostatic interactions in the region close to the mutation site are altered. PCA results indicate that the R123H replacement alter the internal molecular motions of the enzyme and that collective motions are increased. Electrostatic surface potential studies suggest that after mutation the interfacial binding to anionic phospholipid membranes and anionic proteins may be changed. The strengthening of electrostatic interactions may be propagated into the active site region thus potentially affecting the substrate recognition and enzymatic activity. Our findings provide the basis for further investigation and advances our understanding of the effects of mutations on sPLA2 structure and function.

Acute downregulation of miR-199a attenuates sepsis-induced acute lung injury by targeting SIRT1.

MicroRNA-199a (miR-199a) is a novel gene regulator with an important role in inflammation and lung injury. However, its role in the pathogenesis of sepsis-induced acute respiratory distress syndrome (ARDS) is currently unknown. Our study explored the role of miR-199a in sepsis-induced ARDS and its mechanism of action. First, we found that LPS could upregulate miR-199a in alveolar macrophages. Downregulation of miR-199a inhibited the upregulation of inflammatory cytokines in alveolar macrophages and induced the remission of histopathologic changes, the reduction of proinflammatory cytokines, and the upregulation of apoptosis protein expression in an ARDS lung, showing a protective role for miR-199a. We further identified sirtuin 1 (SIRT1) as a direct target of miR-199a in alveolar macrophages, and the expression of SIRT1 was negatively correlated with the level of miR-199a. The protective role of miR-199a downregulation in LPS-stimulated alveolar macrophages and sepsis-induced ARDS could be attenuated by SIRT1 inhibitor. Taken together, these results indicate that downregulation of miR-199a might protect lung tissue against sepsis-induced ARDS by upregulation of SIRT1 through the suppression of excessive inflammatory responses and the inhibition of cellular apoptosis in lung tissue, suggesting its potential therapeutic effects on sepsis-induced ARDS.