Inhibition of a Microbiota-Derived Peptide Ameliorates Established Acute Lung Injury

Abstract

Acute lung injury (ALI) is a clinical syndrome characterized by a diffuse lung inflammation that commonly evolves into acute respiratory distress syndrome and respiratory failure. The lung microbiota is involved in the pathogenesis of ALI. Corisin, a proapoptotic peptide derived from the lung microbiota, plays a role in ALI and acute exacerbation of pulmonary fibrosis. Preventive therapeutic intervention with a monoclonal anticorisin antibody inhibits ALI in mice. However, whether inhibition of corisin with the antibody ameliorates established ALI is unknown. Here, the therapeutic effectiveness of the anticorisin antibody in already established ALI in mice was assessed. Lipopolysaccharide was used to induce ALI in mice. After causing ALI, the mice were treated with a neutralizing anticorisin antibody. Mice treated with the antibody showed significant improvement in lung radiological and histopathologic findings, decreased lung infiltration of inflammatory cells, reduced markers of lung tissue damage, and inflammatory cytokines in bronchoalveolar lavage fluid compared with untreated mice. In addition, the mice treated with anticorisin antibody showed significantly increased expression of antiapoptotic proteins with decreased caspase-3 activation in the lungs compared with control mice treated with an irrelevant antibody. In conclusion, these observations suggest that the inhibition of corisin is a novel and promising approach for treating established ALI. Acute lung injury (ALI) is a clinical syndrome characterized by a diffuse lung inflammation that commonly evolves into acute respiratory distress syndrome and respiratory failure. The lung microbiota is involved in the pathogenesis of ALI. Corisin, a proapoptotic peptide derived from the lung microbiota, plays a role in ALI and acute exacerbation of pulmonary fibrosis. Preventive therapeutic intervention with a monoclonal anticorisin antibody inhibits ALI in mice. However, whether inhibition of corisin with the antibody ameliorates established ALI is unknown. Here, the therapeutic effectiveness of the anticorisin antibody in already established ALI in mice was assessed. Lipopolysaccharide was used to induce ALI in mice. After causing ALI, the mice were treated with a neutralizing anticorisin antibody. Mice treated with the antibody showed significant improvement in lung radiological and histopathologic findings, decreased lung infiltration of inflammatory cells, reduced markers of lung tissue damage, and inflammatory cytokines in bronchoalveolar lavage fluid compared with untreated mice. In addition, the mice treated with anticorisin antibody showed significantly increased expression of antiapoptotic proteins with decreased caspase-3 activation in the lungs compared with control mice treated with an irrelevant antibody. In conclusion, these observations suggest that the inhibition of corisin is a novel and promising approach for treating established ALI. Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS), are diffuse injury of alveolar epithelial cells and pulmonary capillary endothelial cells that disrupts the alveolar epithelial-endothelial barrier, leading to impaired gas exchange and acute hypoxic respiratory failure.1Bernard G.R. Artigas A. Brigham K.L. Carlet J. Falke K. Hudson L. Lamy M. Legall J.R. Morris A. Spragg R. The American-European consensus conference on ARDS. definitions, mechanisms, relevant outcomes, and clinical trial coordination.Am J Respir Crit Care Med. 1994; 149: 818-824Crossref PubMed Scopus (5404) Google Scholar,2Matthay M.A. Zemans R.L. Zimmerman G.A. Arabi Y.M. Beitler J.R. Mercat A. Herridge M. Randolph A.G. Calfee C.S. Acute respiratory distress syndrome.Nat Rev Dis Primers. 2019; 5: 18Crossref PubMed Scopus (625) Google Scholar The presence of hyaline membrane, edema, neutrophil infiltration, fibrin deposition, alveolar collapse, and increased apoptosis of alveolar epithelial cells and capillary endothelial cells are characteristic histopathologic findings in ALI/ARDS.1Bernard G.R. Artigas A. Brigham K.L. Carlet J. Falke K. Hudson L. Lamy M. Legall J.R. Morris A. Spragg R. The American-European consensus conference on ARDS. definitions, mechanisms, relevant outcomes, and clinical trial coordination.Am J Respir Crit Care Med. 1994; 149: 818-824Crossref PubMed Scopus (5404) Google Scholar,2Matthay M.A. Zemans R.L. Zimmerman G.A. Arabi Y.M. Beitler J.R. Mercat A. Herridge M. Randolph A.G. Calfee C.S. Acute respiratory distress syndrome.Nat Rev Dis Primers. 2019; 5: 18Crossref PubMed Scopus (625) Google Scholar The most frequent causative factors of ALI/ARDS are pulmonary infection (35%; eg, bacteria, viruses, and fungi), nonpulmonary sepsis (30%; eg, peritonitis and urinary tract or skin infection), aspiration (10%; eg, gastric juice), and trauma (10%; eg, burning, blunt injury).3Pham T. Rubenfeld G.D. Fifty years of research in ARDS: the epidemiology of acute respiratory distress syndrome: a 50th birthday review.Am J Respir Crit Care Med. 2017; 195: 860-870Crossref PubMed Scopus (156) Google Scholar Newly emerging causes of ALI/ARDS are lung injury associated with an e-cigarette, vaping, chemotherapy, immunotherapy (eg, checkpoint inhibitors), and periodic outbreaks of infection by new strains of virus, including the severe acute respiratory syndrome coronavirus (SARS-Co-V), H1N1 influenza, Middle East respiratory syndrome coronavirus, and SARS-Co-V2.3Pham T. Rubenfeld G.D. Fifty years of research in ARDS: the epidemiology of acute respiratory distress syndrome: a 50th birthday review.Am J Respir Crit Care Med. 2017; 195: 860-870Crossref PubMed Scopus (156) Google Scholar This latter is the cause of the ongoing coronavirus disease 2019 (COVID-19) pandemic. Under nonoutbreak conditions, the annual number of patients with ALI/ARDS worldwide varies between 1 and 5 million and underlies approximately 10% of all admissions to the intensive care unit.3Pham T. Rubenfeld G.D. Fifty years of research in ARDS: the epidemiology of acute respiratory distress syndrome: a 50th birthday review.Am J Respir Crit Care Med. 2017; 195: 860-870Crossref PubMed Scopus (156) Google Scholar, 4Bellani G. Laffey J.G. Pham T. Fan E. Brochard L. Esteban A. Gattinoni L. van Haren F. Larsson A. McAuley D.F. Ranieri M. Rubenfeld G. Thompson B.T. Wrigge H. Slutsky A.S. Pesenti A. Investigators L.S. Group E.T. Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries.JAMA. 2016; 315: 788-800Crossref PubMed Scopus (2949) Google Scholar, 5Fan E. Brodie D. Slutsky A.S. Acute respiratory distress syndrome: advances in diagnosis and treatment.JAMA. 2018; 319: 698-710Crossref PubMed Scopus (830) Google Scholar, 6Rubenfeld G.D. Caldwell E. Peabody E. Weaver J. Martin D.P. Neff M. Stern E.J. Hudson L.D. Incidence and outcomes of acute lung injury.N Engl J Med. 2005; 353: 1685-1693Crossref PubMed Scopus (2937) Google Scholar, 7Sweatt A.J. Levitt J.E. Evolving epidemiology and definitions of the acute respiratory distress syndrome and early acute lung injury.Clin Chest Med. 2014; 35: 609-624Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar The number of annual deaths for ALI/ARDS is approximately 200,000 in the United States.6Rubenfeld G.D. Caldwell E. Peabody E. Weaver J. Martin D.P. Neff M. Stern E.J. Hudson L.D. Incidence and outcomes of acute lung injury.N Engl J Med. 2005; 353: 1685-1693Crossref PubMed Scopus (2937) Google Scholar The mainstay of treatment for ALI/ARDS is lung-protective mechanical ventilation. Adjunctive therapies include treatment of the underlying cause, prone positioning, lung recruitment maneuvers, corticosteroids, extracorporeal membrane oxygenation, and CO2 removal.2Matthay M.A. Zemans R.L. Zimmerman G.A. Arabi Y.M. Beitler J.R. Mercat A. Herridge M. Randolph A.G. Calfee C.S. Acute respiratory distress syndrome.Nat Rev Dis Primers. 2019; 5: 18Crossref PubMed Scopus (625) Google Scholar,5Fan E. Brodie D. Slutsky A.S. Acute respiratory distress syndrome: advances in diagnosis and treatment.JAMA. 2018; 319: 698-710Crossref PubMed Scopus (830) Google Scholar,8Gorman E.A. O'Kane C.M. McAuley D.F. Acute respiratory distress syndrome in adults: diagnosis, outcomes, long-term sequelae, and management.Lancet. 2022; 400: 1157-1170Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar,9Wheeler A.P. Bernard G.R. Acute lung injury and the acute respiratory distress syndrome: a clinical review.Lancet. 2007; 369: 1553-1564Abstract Full Text Full Text PDF PubMed Scopus (723) Google Scholar However, despite these recent advances in therapeutic modalities, the mortality rate of patients with ALI/ARDS remains high. The intrahospital mortality is 34.9% in patients with mild ALI/ARDS, 40% in those with moderate disease, and 46.1% in patients with severe disease.4Bellani G. Laffey J.G. Pham T. Fan E. Brochard L. Esteban A. Gattinoni L. van Haren F. Larsson A. McAuley D.F. Ranieri M. Rubenfeld G. Thompson B.T. Wrigge H. Slutsky A.S. Pesenti A. Investigators L.S. Group E.T. Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries.JAMA. 2016; 315: 788-800Crossref PubMed Scopus (2949) Google Scholar Survivors of ALI/ARDS also continue to have a poor health-related quality of life; very few of them return to their original work several months after hospital discharge.10Carson S.S. Bach P.B. The epidemiology and costs of chronic critical illness.Crit Care Clin. 2002; 18: 461-476Abstract Full Text Full Text PDF PubMed Scopus Google Scholar, C.M. G. A. A. F. D. Slutsky A.S. Herridge outcomes, care and costs of of acute respiratory distress J Respir Crit Care Med. PubMed Scopus Google Scholar, L. S.S. L.S. J.R. and outcomes of in of critical illness.Crit Care Med. 2018; PubMed Scopus Google Scholar is an to new therapeutic for patients with and clinical in the that or of the the or microbiota is involved in the pathogenesis of critical including G.D. 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G. for acute respiratory distress syndrome and for 2019; PubMed Scopus Google Scholar Here, whether inhibition of corisin the increased of these markers in established ALI was all these markers were increased in and lung tissue from mice compared with mice the disease However, mice with ALI treated with the anticorisin showed significantly decreased of and reduced of and in and lung tissue compared with mice with ALI treated with the control cytokines and including and critical in the pathogenesis of Martin D.P. A. Hudson L.D. Martin cytokines in patients with of the acute respiratory distress J Respir Crit Care Med. PubMed Scopus Google J. J. cytokines in the inflammatory of patients with acute respiratory distress syndrome and J. 18: PubMed Scopus Google Scholar all these markers were significantly increased in mice with ALI treated with control compared with the However, mice with ALI treated with anticorisin significantly decreased and lung tissue of and compared with mice with ALI treated with control The of was also decreased in the compared with the the to a significant apoptosis is by the proteins and by of the of apoptosis of of these factors was to the of corisin inhibition on their The of the factors or apoptosis or of apoptosis or of apoptosis and or of apoptosis were significantly increased in the lung tissue from mice with ALI treated with anticorisin compared with mice treated with the control the the proapoptotic was significantly the was significantly in mice treated with the anticorisin compared with mice treated with control by the or M. in the the Rev 2019; PubMed Scopus Google Scholar of of these to activation and of The the caspase-3 in mice with ALI treated with or anticorisin with control of caspase-3 was significantly increased in mice with ALI treated with control However, mice with ALI treated with the anticorisin showed significantly decreased caspase-3 compared with mice with ALI treated with control and caspase-3 was between In addition, the of by the was The of was significantly in mice with ALI treated with irrelevant compared with control mice ALI treated with However, the of was significantly decreased in mice with ALI treated with anticorisin compared with mice with ALI treated with irrelevant and The the that injury the lung microbiota by the of with of of corisin or the of corisin and the and of and corisin were several after of and from mice of were used The of and the and of corisin significantly increased on the after The of and the and of corisin also increased on the and after the This that inhibition of a lung proapoptotic ameliorates radiological findings, inflammatory and apoptosis in established ALI in mice. of the in the pathogenesis of R. A. H. J. M. G. F. M. J. L.D. The of and lung in the PubMed Scopus Google Scholar have of the lung in patients with critical lung K. M. Calfee C.S. microbiota is to and to of acute respiratory distress syndrome in trauma J Respir Crit Care Med. 2018; PubMed Scopus Google J.R. of the lung with in sepsis and the acute respiratory distress syndrome.Nat 2016; PubMed Scopus Google Scholar The lung microbiota and an of and with the of from (eg, K. M. Calfee C.S. microbiota is to and to of acute respiratory distress syndrome in trauma J Respir Crit Care Med. 2018; PubMed Scopus Google J.R. of the lung with in sepsis and the acute respiratory distress syndrome.Nat 2016; PubMed Scopus Google Scholar However, that is a peptide in the of from the lung tissue of mice the in the T. T. M. H. H. A. K. T. A. K. A. A. M. J. T. K. J. H. peptide acute exacerbation of pulmonary PubMed Scopus Google T. T. M. H. H. A. K. T. H. A. M. A. R. J. M. T. D. K. M. T. of lung proapoptotic ameliorates acute exacerbation of pulmonary 2022; PubMed Scopus Google Scholar showed that the corisin is in a of and strains of T. T. M. H. H. A. K. T. A. K. A. A. M. J. T. K. J. H. peptide acute exacerbation of pulmonary PubMed Scopus Google Scholar the corisin or in bacteria, including and and bacteria, including and T. T. M. H. H. A. K. T. A. K. A. A. M. J. T. K. J. H. peptide acute exacerbation of pulmonary PubMed Scopus Google T. T. M. H. H. A. K. T. H. A. M. A. R. J. M. T. D. K. M. T. of lung proapoptotic ameliorates acute exacerbation of pulmonary 2022; PubMed Scopus Google Scholar acute exacerbation of pulmonary by apoptosis of lung epithelial The corisin is a of by induce T. T. M. H. H. A. K. T. A. K. A. A. M. J. T. K. J. H. peptide acute exacerbation of pulmonary PubMed Scopus Google Scholar peptide is a in a The of peptide in and from patients with pulmonary with acute exacerbation and inhibition of lung epithelial apoptosis by with anticorisin neutralizing antibody the clinical of corisin in T. T. M. H. H. A. K. T. A. K. A. A. M. J. T. K. J. H. peptide acute exacerbation of pulmonary PubMed Scopus Google T. T. M. H. H. A. K. T. H. A. M. A. R. J. M. T. D. K. M. T. of lung proapoptotic ameliorates acute exacerbation of pulmonary 2022; PubMed Scopus Google H. T. M. A. T. K. M. H. K. T. peptide apoptosis of cells from PubMed Scopus Google Scholar corisin also in from mice and that corisin also a role in the pathogenesis of lung T. T. M. H. H. A. K. T. A. K. A. A. M. J. T. K. J. H. peptide acute exacerbation of pulmonary PubMed Scopus Google T. T. M. H. H. A. K. T. H. A. M. A. R. J. M. T. D. K. M. T. of lung proapoptotic ameliorates acute exacerbation of pulmonary 2022; PubMed Scopus Google Scholar In the the that corisin a therapeutic in ALI/ARDS was that of mice with an anticorisin monoclonal antibody ALI by of is associated with significant of radiological and inflammatory in the corisin in the of T. T. M. H. H. A. K. T. H. A. M. A. R. J. M. T. D. K. M. T. of lung proapoptotic ameliorates acute exacerbation of pulmonary 2022; PubMed Scopus Google Scholar However, whether the anticorisin is in already established ALI/ARDS is or are to the the disease already In the ALI in mice was by of and treatment with anticorisin was The of radiological findings, the infiltration of the expression of inflammatory and the expression of markers of acute tissue injury were significantly in mice with ALI treated with the anticorisin compared with their treated with an irrelevant antibody. findings the role of corisin in ALI and to corisin a for treating and clinical the role of apoptosis of lung epithelial and endothelial cells in the pathogenesis of E. endothelial apoptosis in and acute lung 2018; PubMed Scopus Google Scholar, E. M. M. G. The role of apoptosis in the of acute respiratory distress syndrome an PubMed Scopus Google Scholar, M. G. and epithelial injury in the 2005; PubMed Scopus Google Scholar by the and in M. in the the Rev 2019; PubMed Scopus Google Scholar are of increased expression of proapoptotic proteins and and activation of the proapoptotic in the alveolar from patients with E. M. M. G. The role of apoptosis in the of acute respiratory distress syndrome an PubMed Scopus Google A. Zimmerman G.A. M.A. and are in pulmonary fluid and lung tissue of patients with acute lung injury and the acute respiratory distress J 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, S.S. is a for the of in acute lung J 149: Google Scholar, D. E. M. T. M. M. The role of and expression in diffuse alveolar J Google Scholar, S.S. of bronchoalveolar lavage fluid from patients with to Med. Full Text Full Text PDF PubMed Scopus Google Scholar of endothelial cells also in patients with and of E. endothelial apoptosis in and acute lung 2018; PubMed Scopus Google E. M. M. G. The role of apoptosis in the of acute respiratory distress syndrome an PubMed Scopus Google D. D. J. by apoptosis and in pulmonary endothelial cells the J Med. 2017; Google Scholar The from patients with is to endothelial J. R. A. and are of endothelial in bronchoalveolar of patients with acute respiratory distress J Respir Crit Care Med. 2002; PubMed Scopus Google Scholar and apoptosis of endothelial cells the of the pulmonary leading to and M.A. Zemans R.L. Zimmerman G.A. Arabi Y.M. Beitler J.R. Mercat A. Herridge M. Randolph A.G. Calfee C.S. Acute respiratory distress syndrome.Nat Rev Dis Primers. 2019; 5: 18Crossref PubMed Scopus (625) Google Scholar The cause of is M.A. The acute respiratory distress Engl J Med. PubMed Scopus Google Scholar is a peptide that apoptosis of epithelial cells from was that of mice with corisin of ALI with the inflammatory in the T. T. M. H. H. A. K. T. H. A. M. A. R. J. M. T. D. K. M. T. of lung proapoptotic ameliorates acute exacerbation of pulmonary 2022; PubMed Scopus Google Scholar However, whether inhibition of corisin ameliorates apoptosis in ALI remains In the anticorisin was to mice after ALI by of and and the expression of and proapoptotic factors in lung tissue were assessed. The expression of antiapoptotic including and of was significantly the proapoptotic the and were significantly in mice treated with anticorisin compared with untreated the of the anticorisin the apoptosis by This inhibition of apoptosis with the anticorisin was associated with a reduced lung inflammatory The with a that treatment with a is in a of M. K. T. R. T. T. from apoptosis in acute lung injury in mice by a J Full Text Full Text PDF PubMed Scopus Google Scholar these observations suggest that the anticorisin ALI by apoptosis of lung cells and that the corisin and an role in the The of suggest that corisin is a therapeutic that the anticorisin neutralizing antibody is a promising therapeutic and that inhibition of apoptosis is in established However, in corisin and corisin of anticorisin are to proapoptotic in patients with ALI/ARDS and to and the of corisin In addition, also to of a significant of corisin from the

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