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ABSTRACT: RATIONALE: HIV-1-induced interstitial pneumonitis (IP) is a serious complication of HIV-1 infection, characterized by inflammation, cellular infiltration in lungs, often leading to respiratory failure and death. The barrier function of the pulmonary endothelium is due in part to tight junctions (TJ) proteins such as claudin-5. Peroxisome proliferator-activated receptor (PPAR)-γ is expressed in lung tissues and regulates inflammation. We hypothesize that HIV-1 induces vascular lung injury, and HIV-1-mediated damage of the pulmonary endothelium and IP is associated with dysregulation of PPAR-γ. OBJECTIVES: Investigate the effects of HIV-1 infection on the pulmonary microvasculature and the modulatory effects of the PPAR-γ ligands.Methods and RESULTS: Using human lungs tissues, we demonstrated downregulation of claudin-5 (marker of pulmonary barrier integrity), downregulation of PPAR-γ transcription and expression in lung tissues of HIV-1-infected humans with IP. Human lung microvascular endothelial cells expressed the TJ proteins claudin-5, ZO-1, and ZO-2; HIV-1 decreased TJ proteins expression and induced NFκB promoter activity, which was reversed by PPAR-γ agonist. Using two murine HIV/AIDS models, we demonstrated decreased claudin-5 expression and increased macrophage infiltration in the lungs of HIV-1-infected animals. Activation of PPAR-γ prevented HIV-1-induced claudin-5 downregulation, significantly reduced viremia and pulmonary macrophage infiltration. CONCLUSION: HIV-induced IP is associated with injury to the lung vascular endothelium, with decreased TJ and PPAR-γ expression, and increased pulmonary macrophage infiltration. PPAR-γ ligands abrogated these effects. Thus, regulation of PPAR-γ can be a therapeutic approach against HIV-1-induced vascular damage and IP in infected humans.
American Journal of Respiratory and Critical Care Medicine 02/2012; · 11.08 Impact Factor
