Adiposity and airway inflammation in HIV-associated airway disease

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

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Abstract

? DESCRIPTION (provided by applicant): Despite the high burden of morbidity and mortality from asthma in the general population, it is relatively understudied in the HIV-infected population. We have found a prevalence of doctor-diagnosed asthma in an HIV-infected cohort of 21%, much higher than in the general population, and asthma may overlap with other obstructive lung diseases which are also found frequently in HIV. Pathogenesis of asthma in HIV is not understood, but obesity is implicated in asthma in the general population. HIV-infected individuals may have more advanced metabolic derangements at a lesser degree of obesity due to HIV-associated systemic inflammation, lipodystrophy, and side effects of antiretroviral medication. We have found that obesity is a risk factor for doctor-diagnosed asthma in HIV with obese HIV-infected persons having 2.3 times the odds of having an asthma diagnosis compared to non-obese HIV-infected persons. We also find that thickened airway walls (a sign of airway remodeling associated with asthma) strongly correlate with body mass index. Our preliminary data demonstrate that the etiology of asthma in HIV may involve obesity-related inflammatory pathways rather than a typical Th2/allergic response. Obesity-related inflammation and its effects on lung inflammation may be an important phenotype and mechanism in HIV-related asthma. One key metabolic factor associated with both obesity and HIV is increased asymmetric dimethylarginine (ADMA) which is a product of L-arginine methylation, inhibits and uncouples nitric oxide synthase, and may be pathogenic in the late-onset asthma phenotype in the general population. We hypothesize that adiposity contributes to a non-Th2 phenotype of asthma and airway remodeling in HIV as a consequence of obesity-related inflammation and oxidative stress from high ADMA. We will test this hypothesis with the following aims: 1) to test the hypothesis that there is an adverse interaction of adiposity and HIV-associated inflammation in asthma susceptibility and airway remodeling in HIV. In this aim, we will determine the relationship between adiposity and asthma as well as airway remodeling determined by quantitative airway measures captured from computed tomography scan and histologic examination from endobronchial biopsies in subgroups of participants defined by the presence of asthma and obesity. 2) To test the hypothesis that adipose tissue- related inflammation contributes to asthma susceptibility and airway remodeling in HIV. Inflammatory mediators will be measured directly from adipose tissue biopsies. 3) To test the hypothesis that low L- arginine/ADMA increases asthma risk and airway remodeling in HIV. Understanding causes of asthma in HIV is important in developing appropriate treatment as no standard pharmacologic therapies have been tested specifically in HIV asthma and available asthma medications may have more side effects in HIV than in the general population. (End of Abstract)