Effect of Cocaine on HIV-mediated Pulmonary Endothelial and Smooth Muscle Dysfunction

Human immunodeficiency virus-associated pulmonary arterial hypertension (HIV-PAH) is a devastating non-infectious complication of acquired immune deficiency syndrome and the majority of HIV-PAH cases occur in individuals with a history of intravenous drug use (IVDU). But although HIV-1 and IVDU have been associated with PAH independently or in combination, the pathogenesis of HIV-PAHâs disproportionate presence in IVDUs has yet to be characterized. The objective of this study was to obtain a better understanding of the interactions between HIV-1 and cocaine in order to help uncover the mechanism(s) of HIV-PAHâs development. We observed that exposure of HIV-infected macrophages or HIV-Tat treated pulmonary endothelial cells to cocaine enhanced the expression of platelet-derived growth factor (PDGF)-BB, while simultaneous treatment with Tat and cocaine exacerbated both the disruption of tight junction proteins (TJPs) with enhanced permeability in pulmonary endothelial cells and the proliferation of pulmonary smooth muscle cells (pSMCs) compared to either treatment alone. Histological examination of HIV+IVDU human lung sections showed signs of early pulmonary arteriopathy, severe down-modulation of TJPs and increased expression of PDGF-BB compared to the lung sections from HIV-infected non-IVDUs. Interestingly, blocking of PDGF-receptor signaling with the receptor antagonist or small interfering RNA has been shown to inhibit the increase in proliferation of pSMCs on Tat and cocaine exposure. Our results therefore support an additive effect of cocaine to HIV-infection in the development of pulmonary arteriopathy through enhancement of endothelial dysfunction and proliferation of pSMCs, while also suggesting PDGF/PDGF-receptor axis as a potential target for use in clinical intervention.