Plasminogen activator inhibitor-1 in cigarette smoke exposure and influenza A virus infection-induced lung injury.
Parenchymal lung inflammation and airway and alveolar epithelial cell apoptosis are associated with cigarette smoke exposure (CSE), which contributes to chronic obstructive pulmonary disease (COPD). Epidemiological studies indicate that people exposed to chronic cigarette smoke with or without COPD are more susceptible to influenza A virus (IAV) infection. We found increased p53, PAI-1 and apoptosis in AECs, with accumulation of macrophages and neutrophils in the lungs of patients with COPD. In Wild-type (WT) mice with passive CSE (PCSE), p53 and PAI-1 expression and apoptosis were increased in AECs as was lung inflammation, while those lacking p53 or PAI-1 resisted AEC apoptosis and lung inflammation. Further, inhibition of p53-mediated induction of PAI-1 by treatment of WT mice with caveolin-1 scaffolding domain peptide (CSP) reduced PCSE-induced lung inflammation and reversed PCSE-induced suppression of eosinophil-associated RNase1 (EAR1). Competitive inhibition of the p53-PAI-1 mRNA interaction by expressing p53-binding 3'UTR sequences of PAI-1 mRNA likewise suppressed CS-induced PAI-1 and AEC apoptosis and restored EAR1 expression. Consistent with PCSE-induced lung injury, IAV infection increased p53, PAI-1 and apoptosis in AECs in association with pulmonary inflammation. Lung inflammation induced by PCSE was worsened by subsequent exposure to IAV. Mice lacking PAI-1 that were exposed to IAV showed minimal viral burden based on M2 antigen and hemagglutination analyses, whereas transgenic mice that overexpress PAI-1 without PCSE showed increased M2 antigen and inflammation after IAV infection. These observations indicate that increased PAI-1 expression promotes AEC apoptosis and exacerbates lung inflammation induced by IAV following PCSE.
Texas Lung Injury Institute, Department of Medicine, University of Texas Health Science Center at Tyler, Tyler, Texas, United States of America.
Yashodhar P
YP
Bhandary
Texas Lung Injury Institute, Department of Medicine, University of Texas Health Science Center at Tyler, Tyler, Texas, United States of America.
Shwetha K
SK
Shetty
Texas Lung Injury Institute, Department of Medicine, University of Texas Health Science Center at Tyler, Tyler, Texas, United States of America.
Amarnath S
AS
Marudamuthu
Texas Lung Injury Institute, Department of Medicine, University of Texas Health Science Center at Tyler, Tyler, Texas, United States of America.
Krishna K
KK
Midde
Texas Lung Injury Institute, Department of Medicine, University of Texas Health Science Center at Tyler, Tyler, Texas, United States of America.
Hong-Long
HL
Ji
Texas Lung Injury Institute, Department of Medicine, University of Texas Health Science Center at Tyler, Tyler, Texas, United States of America.
Homoyoun
H
Shams
Texas Lung Injury Institute, Department of Medicine, University of Texas Health Science Center at Tyler, Tyler, Texas, United States of America.
Renuka
R
Subramaniam
Center for Research on Environmental Disease and Toxicology, College of Medicine, University of Kentucky, Lexington, Kentucky, United States of America.
Jian
J
Fu
Texas Lung Injury Institute, Department of Medicine, University of Texas Health Science Center at Tyler, Tyler, Texas, United States of America.
Steven
S
Idell
Texas Lung Injury Institute, Department of Medicine, University of Texas Health Science Center at Tyler, Tyler, Texas, United States of America.
Sreerama
S
Shetty
D056809:Alveolar Epithelial Cells / Q000187:drug effects / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051242:Caveolin 1 / Q000494:pharmacology; D006801:Humans; D009980:Influenza A virus / Q000187:drug effects / Q000502:physiology*; D007251:Influenza, Human / Q000150:complications* / Q000473:pathology / Q000821:virology; D019272:Leukocyte Elastase / Q000378:metabolism; D008156:Luciferases / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D055370:Lung Injury / Q000209:etiology / Q000821:virology*; D008810:Mice, Inbred C57BL; D009976:Orthomyxoviridae Infections / Q000150:complications* / Q000473:pathology / Q000821:virology; D010446:Peptide Fragments / Q000494:pharmacology; D009195:Peroxidase / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D029424:Pulmonary Disease, Chronic Obstructive / Q000378:metabolism / Q000473:pathology; D012907:Smoking; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D051242:Caveolin 1; D010446:Peptide Fragments; D017395:Plasminogen Activator Inhibitor 1; D016159:Tumor Suppressor Protein p53; C571371:caveolin-1 (82-101); D009195:Peroxidase; D008156:Luciferases; D019272:Leukocyte Elastase