Core genes involved in the regulation of acute lung injury and their association with COVID-19 and tumor progression: A bioinformatics and experimental study.

Innokenty A. Savin,Evgenyi V. Brenner,Andrey V. Markov,Marina A. Zenkova,You-Yang Zhao,Aleksandra V. Sen’kova

doi:10.1371/journal.pone.0260450

Abstract

Acute lung injury (ALI) is a specific form of lung damage caused by different infectious and non-infectious agents, including SARS-CoV-2, leading to severe respiratory and systemic inflammation. To gain deeper insight into the molecular mechanisms behind ALI and to identify core elements of the regulatory network associated with this pathology, key genes involved in the regulation of the acute lung inflammatory response (Il6, Ccl2, Cat, Serpine1, Eln, Timp1, Ptx3, Socs3) were revealed using comprehensive bioinformatics analysis of whole-genome microarray datasets, functional annotation of differentially expressed genes (DEGs), reconstruction of protein-protein interaction networks and text mining. The bioinformatics data were validated using a murine model of LPS-induced ALI; changes in the gene expression patterns were assessed during ALI progression and prevention by anti-inflammatory therapy with dexamethasone and the semisynthetic triterpenoid soloxolone methyl (SM), two agents with different mechanisms of action. Analysis showed that 7 of 8 revealed ALI-related genes were susceptible to LPS challenge (up-regulation: Il6, Ccl2, Cat, Serpine1, Eln, Timp1, Socs3; down-regulation: Cat) and their expression was reversed by the pre-treatment of mice with both anti-inflammatory agents. Furthermore, ALI-associated nodal genes were analysed with respect to SARS-CoV-2 infection and lung cancers. The overlap with DEGs identified in postmortem lung tissues from COVID-19 patients revealed genes (Saa1, Rsad2, Ifi44, Rtp4, Mmp8) that (a) showed a high degree centrality in the COVID-19-related regulatory network, (b) were up-regulated in murine lungs after LPS administration, and (c) were susceptible to anti-inflammatory therapy. Analysis of ALI-associated key genes using The Cancer Genome Atlas showed their correlation with poor survival in patients with lung neoplasias (Ptx3, Timp1, Serpine1, Plaur). Taken together, a number of key genes playing a core function in the regulation of lung inflammation were found, which can serve both as promising therapeutic targets and molecular markers to control lung ailments, including COVID-19-associated ALI.

Highlights

Acute lung injury (ALI), clinically followed by the acute respiratory distress syndrome (ARDS), is a specific form of lung injury characterised by diffuse alveolar damage, non-cardiogenic pulmonary oedema, pulmonary and systemic neutrophil-associated inflammation, resulting in respiratory failure and hypoxemia [1,2,3,4]
Given the revealed enrichment in terms associated with virusinduced immune responses as well as the known involvement of G protein-coupled receptor (GPCR) signalling in the progression of numerous inflammatory disorders [83], our analysis clearly shows the probable regulatory role of a range of ALI-related differentially expressed genes (DEGs) in lung injury mediated by SARS-CoV-2 infection
The integrative bioinformatics analysis of four independent ALI-associated cDNA microarray datasets with subsequent verification using RT-PCR data revealed a set of core genes involved in the regulation of acute pulmonary inflammation in mice, which play a key regulatory role in ARDS induced by COVID-19 and lung adenocarcinoma (LUAD)/lung squamous cell carcinoma (LUSC) progression in humans

Summary

Introduction

Acute lung injury (ALI), clinically followed by the acute respiratory distress syndrome (ARDS), is a specific form of lung injury characterised by diffuse alveolar damage, non-cardiogenic pulmonary oedema, pulmonary and systemic neutrophil-associated inflammation, resulting in respiratory failure and hypoxemia [1,2,3,4]. ALI can be caused by different phlogogens and irritants, such as bacterial and viral pathogens [9,10,11,12], chemicals such as chlorine and phosgene [13, 14], and industrial aerosols [15]. At the present time, the most common causative agent of ALI is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, resulting in pneumonia and ARDS [16]. Exposure to different chemical agents can induce a unique mix of physiologic derangements leading to pathology, similar to the acute phase of ARDS. The most prevalent methods of ALI induction are bacterial lipopolysaccharide (LPS) [17, 18] or bleomycin [19] injection, hyperoxic injury [20], and influenza virus infection [21]. LPS, a major component of the outer membrane of Gram-negative bacteria and a prominent inducer of local and systemic inflammatory responses, is closely related to lung injury and has often been employed to induce pulmonary inflammation in ALI in vivo models [22,23,24]

Methods

Results

Discussion

Conclusion