Despite the increased survival of individuals with HIV-1 (HIV) infection resulting from the use of highly active antiretroviral therapy (HAART), individuals infected with HIV have an increased risk for the development of chronic obstructive pulmonary disease, manifesting as emphysema. The emphysema occurs at an earlier age than in HIV- smokers, and is recognized as an increasing cause of morbidity in the HAART-treated HIV+ population. The pathogenesis of HIV-associated emphysema has been hypothesized to result from an exaggerated lower respiratory tract burden of inflammatory cell-derived proteases and/or oxidants, direct effects of HIV proteins, or adverse effects of anti- retroviral therapy. Despite evidence to support each of these mechanisms, there is limited data in humans pointing to specific molecular targets that contribute to the destruction of the lower respiratory tract leading to emphysema. Based on preliminary data generated from HIV+ individuals, we will use a multidisciplinary approach to explore the hypothesis that the combination of HIV infection and smoking activates alveolar macrophages (AM) to create chronic oxidant stress in the lower respiratory tract that promotes apoptosis of the pulmonary capillary endothelium, contributing to progressive alveolar destruction. We will study this hypothesis by sampling HIV+ and HIV- subjects for AM and lower respiratory tract epithelial lining fluid (ELF) by bronchoalveolar lavage, and by assessing plasma pulmonary capillary-derived endothelial microparticles (EMPs) as a biomarker for ongoing pulmonary capillary endothelial apoptosis. Using newly developed mass spectrometry methodologies, we will quantify the oxidant stress of AM, ELF and plasma EMPs, and identify specific oxidized metabolites within each of these compartments. Finally, we will model the AM-pulmonary capillary endothelial interaction in vitro to tease apart the contribution of each component of the interaction. We will assess HIV+ and HIV- nonsmokers, smokers, smokers with early and GOLD criteria emphysema using 3 specific aims.
Aim 1. To explore the extent of oxidant stress in the lower respiratory tract of HIV+ and HIV- subjects by assessing spontaneous AM generation of oxidants, together with mass spectrometry-based assessment of the oxidation state of AM and lower respiratory tract ELF.
Aim 2. To evaluate the plasma levels of pulmonary capillary apoptosis-derived EMPs of HIV+ nonsmokers and smokers, and to assess the oxidation state of the components of these EMPs.
Aim 3. To examine the interaction of pulmonary capillary endothelium with AM of HIV+ and HIV- subjects, using apoptosis and the oxidation state of endothelial metabolites as the phenotype of the interaction. As we develop data to solidify our hypothesis, we expect to uncover a new class of targets to test drugs aimed at preventing HIV-associated emphysema.
Chronic HIV infection is associated with a high incidence of emphysema, a significant cause of morbidity despite treatment with antiretroviral drugs. Based on the knowledge that HIV can infect and activate alveolar macrophages (AM), the lung representative of the mononuclear phagocyte system, we hypothesize that HIV infection of AM results in a chronic, exaggerated oxidant stress in the lower respiratory tract that mediates programmed cell death of the pulmonary capillary endothelium, contributing to the development of emphysema.