title: p53- and PAI-1-mediated induction of C-X-C chemokines and CXCR2: importance in pulmonary inflammation due to cigarette smoke exposure.
abstract: We previously demonstrated that tumor suppressor protein p53 augments plasminogen activator inhibitor-1 (PAI-1) expression in alveolar epithelial cells (AECs) during chronic cigarette smoke (CS) exposure-induced lung injury. Chronic lung inflammation with elevated p53 and PAI-1 expression in AECs and increased susceptibility to and exacerbation of respiratory infections are all associated with chronic obstructive pulmonary disease (COPD). We recently demonstrated that preventing p53 from binding to the endogenous PAI-1 mRNA in AECs by either suppressing p53 expression or blockading p53 interactions with the PAI-1 mRNA mitigates apoptosis and lung injury. Within this context, we now show increased expression of the C-X-C chemokines (CXCL1 and CXCL2) and their receptor CXCR2, and the intercellular cellular adhesion molecule-1 (ICAM-1), in the lung tissues of patients with COPD. We also found a similar increase in lung tissues and AECs from wild-type (WT) mice exposed to passive CS for 20 wk and in primary AECs treated with CS extract in vitro. Interestingly, passive CS exposure of mice lacking either p53 or PAI-1 expression resisted an increase in CXCL1, CXCL2, CXCR2, and ICAM-1. Furthermore, inhibition of p53-mediated induction of PAI-1 expression by treatment of WT mice exposed to passive CS with caveolin-1 scaffolding domain peptide reduced CXCL1, CXCL2, and CXCR2 levels and lung inflammation. Our study reveals that p53-mediated induction of PAI-1 expression due to chronic CS exposure exacerbates lung inflammation through elaboration of CXCL1, CXCL2, and CXCR2. We further provide evidence that targeting this pathway mitigates lung injury associated with chronic CS exposure.
authors.affiliation: The Texas Lung Injury Institute, The University of Texas Health Science Center at Tyler, Tyler, Texas; and.
authors.forename: Nivedita
authors.initials: N
authors.lastname: Tiwari
authors.affiliation: The Texas Lung Injury Institute, The University of Texas Health Science Center at Tyler, Tyler, Texas; and.
authors.forename: Amarnath S
authors.initials: AS
authors.lastname: Marudamuthu
authors.affiliation: The Texas Lung Injury Institute, The University of Texas Health Science Center at Tyler, Tyler, Texas; and.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Tsukasaki
authors.affiliation: The Texas Lung Injury Institute, The University of Texas Health Science Center at Tyler, Tyler, Texas; and.
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Ikebe
authors.affiliation: Center for Research on Environmental Disease and Toxicology, College of Medicine, University of Kentucky, Lexington, Kentucky.
authors.forename: Jian
authors.initials: J
authors.lastname: Fu
authors.affiliation: The Texas Lung Injury Institute, The University of Texas Health Science Center at Tyler, Tyler, Texas; and sreerama.shetty@uthct.edu.
authors.forename: Sreerama
authors.initials: S
authors.lastname: Shetty
mesh_terms: D000818:Animals; D054360:Chemokine CXCL1 / Q000378:metabolism*; D054426:Chemokine CXCL2 / Q000378:metabolism*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D029424:Pulmonary Disease, Chronic Obstructive / Q000209:etiology / Q000276:immunology / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000235:genetics / Q000378:metabolism*; D058258:Serpin E2 / Q000502:physiology*; D012906:Smoke / Q000009:adverse effects*; D012907:Smoking / Q000009:adverse effects; D014026:Nicotiana / Q000009:adverse effects; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; C475895:Cxcl1 protein, mouse; C404915:Cxcl2 protein, mouse; D023063:Receptors, Interleukin-8B; D058258:Serpin E2; C511869:Serpine2 protein, mouse; D012906:Smoke; D016159:Tumor Suppressor Protein p53; D018799:Intercellular Adhesion Molecule-1
keywords: COPD; PAI-1; p53; passive cigarette smoke and lung inflammation