title: Critical role of type 1 plasminogen activator inhibitor (PAI-1) in early host defense against nontypeable Haemophilus influenzae (NTHi) infection.
abstract: Respiratory systems are constantly being challenged by pathogens. Lung epithelial cells serve as a first line of defense against microbial pathogens by detecting pathogen-associated molecular patterns (PAMPs) and activating downstream signaling pathways, leading to a plethora of biological responses required for shaping both the innate and adaptive arms of the immune response. Acute-phase proteins (APPs), such as type 1 plasminogen activator inhibitor (PAI-1), play important roles in immune/inflammatory responses. PAI-1, a key regulator for fibrinolysis and coagulation, acts as an APP during acute phase response (APR) such as acute lung injury (ALI), inflammation, and sepsis. However, the role of PAI-1 in the pathogenesis of these diseases still remains unclear, especially in bacterial pneumonia. In this study, we showed that PAI-1 expression is upregulated following nontypeable Haemophilus influenzae (NTHi) infection. PAI-1 knockout (KO) mice failed to generate early immune responses against NTHi. Failure of generating early immune responses in PAI-1 KO mice resulted in reduced bacterial clearance and prolonged disease process, which in turn led to enhanced inflammation at late stage of infection. Moreover, we also found that NTHi induces PAI-1 via activation of TLR2-MyD88-MKK3-p38 MAPK signaling pathway. These data suggest that PAI-1 plays critical role in earl host defense response against NTHi infection. Our study thus reveals a novel role of PAI-1 in infection caused by NTHi, one of the most common gram-negative bacterial pathogens in respiratory systems.
authors.affiliation: Center for Inflammation, Immunity & Infection, and Department of Biology, Georgia State University, Atlanta, GA 30303, USA.
authors.forename: Jae Hyang
authors.initials: JH
authors.lastname: Lim
authors.forename: Chang-Hoon
authors.initials: CH
authors.lastname: Woo
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Li
mesh_terms: D000818:Animals; D006192:Haemophilus Infections / Q000276:immunology*; D006193:Haemophilus influenzae; D006367:HeLa Cells; D054884:Host-Pathogen Interactions / Q000276:immunology*; D006801:Humans; D048371:MAP Kinase Kinase 3 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000502:physiology*; D011650:Pulmonary Alveoli / Q000382:microbiology; D010959:Tissue Plasminogen Activator / Q000378:metabolism; D015854:Up-Regulation; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D048051:p38 Mitogen-Activated Protein Kinases; D048371:MAP Kinase Kinase 3; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator