Dysregulation of Alveolar Macrophage PPARγ, NADPH Oxidases, and TGFβ1in Otherwise Healthy HIV-Infected Individuals.
Despite antiretroviral therapy (ART), respiratory infections increase mortality in individuals living with chronic human immunodeficiency virus (HIV) infection. In experimental and clinical studies of chronic HIV infection, alveolar macrophages (AMs) exhibit impaired phagocytosis and bacterial clearance. Peroxisome proliferator-activated receptor (PPAR)γ, NADPH oxidase (Nox) isoforms Nox1, Nox2, Nox4, and transforming growth factor-beta 1 (TGFβ1) are critical mediators of AM oxidative stress and phagocytic dysfunction. Therefore, we hypothesized that HIV alters AM expression of these targets, resulting in chronic lung oxidative stress and subsequent immune dysfunction. A cross-sectional study of HIV-infected (n = 22) and HIV-uninfected (n = 6) subjects was conducted. Bronchoalveolar lavage (BAL) was performed, and AMs were isolated. Lung H2O2generation was determined by measuring H2O2in the BAL fluid. In AMs, PPARγ, Nox1, Nox2, Nox4, and TGFβ1mRNA (quantitative real-time polymerase chain reaction) and protein (fluorescent immunomicroscopy) levels were assessed. Compared with HIV-uninfected (control) subjects, HIV-infected subjects were relatively older and the majority were African American; ∼86% were on ART, and their median CD4 count was 445, with a median viral load of 0 log copies/ml. HIV infection was associated with increased H2O2in the BAL, decreased AM mRNA and protein levels of PPARγ, and increased AM mRNA and protein levels of Nox1, Nox2, Nox4, and TGFβ1. PPARγ attenuation and increases in Nox1, Nox2, Nox4, and TGFβ1contribute to AM oxidative stress and immune dysfunction in the AMs of otherwise healthy HIV-infected subjects. These findings provide novel insights into the molecular mechanisms by which HIV increases susceptibility to pulmonary infections.
1 Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, Emory University , Atlanta, Georgia .|2 Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Emory + Children's Healthcare of Atlanta Center for Developmental Lung Biology, Emory University , Atlanta, Georgia .
Samantha M
SM
Yeligar
2 Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Emory + Children's Healthcare of Atlanta Center for Developmental Lung Biology, Emory University , Atlanta, Georgia .
Janine M
JM
Ward
2 Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Emory + Children's Healthcare of Atlanta Center for Developmental Lung Biology, Emory University , Atlanta, Georgia .
Frank L
FL
Harris
2 Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Emory + Children's Healthcare of Atlanta Center for Developmental Lung Biology, Emory University , Atlanta, Georgia .
Lou Ann S
LAS
Brown
1 Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, Emory University , Atlanta, Georgia .|3 Atlanta VA Medical Center , Decatur, Georgia .
David M
DM
Guidot
1 Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Department of Medicine, Emory University , Atlanta, Georgia .|3 Atlanta VA Medical Center , Decatur, Georgia .
Sushma K
SK
Cribbs
D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D018791:CD4 Lymphocyte Count; D002478:Cells, Cultured; D003430:Cross-Sectional Studies; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000473:pathology* / Q000821:virology; D006801:Humans; D006861:Hydrogen Peroxide / Q000032:analysis; D016676:Macrophages, Alveolar / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000276:immunology*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D010587:Phagocytosis / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*; D019562:Viral Load
D019380:Anti-HIV Agents; D047495:PPAR gamma; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D006861:Hydrogen Peroxide; D019255:NADPH Oxidases
HIV; immunology; molecular biology