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Effect of cocaine on human immunodeficiency virus-mediated pulmonary endothelial and smooth muscle dysfunction.

ABSTRACT: Human immunodeficiency virus (HIV)-associated pulmonary arterial hypertension (PAH) is a devastating, noninfectious complication of acquired immune deficiency syndrome, and the majority of HIV-PAH cases occur in individuals with a history of intravenous drug use (IVDU). However, although HIV-1 and IVDU have been associated with PAH independently or in combination, the pathogenesis of the disproportionate presence of HIV-PAH in association with IVDU has yet to be characterized. The objective of this study was to obtain a better understanding of the interactions between HIV-1 and cocaine to help uncover the mechanism(s) of the development of HIV-PAH. We observed that exposure of HIV-infected macrophages or HIV-Trans-Activator of Transcription (Tat)-treated pulmonary endothelial cells to cocaine enhanced the expression of platelet-derived growth factor (PDGF)-BB. Simultaneous treatment with Tat and cocaine, on the other hand, 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 with either treatment alone. Histological examination of HIV plus IVDU human lung sections showed signs of early pulmonary arteriopathy, severe down-modulation of TJPs, and increased expression of PDGF-BB compared with the lung sections from individuals who are infected with HIV and without history of IVDU. 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.

SUBMITTER: Dhillon NK

PROVIDER: S-EPMC3145070 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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Effect of cocaine on human immunodeficiency virus-mediated pulmonary endothelial and smooth muscle dysfunction.

Dhillon Navneet K NK Li Fang F Xue Bing B Tawfik Ossama O Morgello Susan S Buch Shilpa S Ladner Amy O'Brien AO

American journal of respiratory cell and molecular biology 20100827 1

Human immunodeficiency virus (HIV)-associated pulmonary arterial hypertension (PAH) is a devastating, noninfectious complication of acquired immune deficiency syndrome, and the majority of HIV-PAH cases occur in individuals with a history of intravenous drug use (IVDU). However, although HIV-1 and IVDU have been associated with PAH independently or in combination, the pathogenesis of the disproportionate presence of HIV-PAH in association with IVDU has yet to be characterized. The objective of t ...[more]

PMID: 20802087

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Project description:Thrombin is a procoagulant inflammatory agonist that can disrupt the endothelium-lumen barrier in the lung by causing contraction of endothelial cells and promote pulmonary cell proliferation. Both contraction and proliferation require increases in cytosolic Ca(2+) concentration ([Ca(2+)](cyt)). In this study, we compared the effect of thrombin on Ca(2+) signaling in human pulmonary artery smooth muscle (PASMC) and endothelial (PAEC) cells. Thrombin increased the [Ca(2+)](cyt) in both cell types; however, the transient response was significantly higher and recovered quicker in the PASMC, suggesting different mechanisms may contribute to thrombin-mediated increases in [Ca(2+)](cyt) in these cell types. Depletion of intracellular stores with cyclopiazonic acid (CPA) in the absence of extracellular Ca(2+) induced calcium transients representative of those observed in response to thrombin in both cell types. Interestingly, CPA pretreatment significantly attenuated thrombin-induced Ca(2+) release in PASMC; this attenuation was not apparent in PAEC, indicating that a PAEC-specific mechanism was targeted by thrombin. Treatment with a combination of CPA, caffeine, and ryanodine also failed to abolish the thrombin-induced Ca(2+) transient in PAEC. Notably, thrombin-induced receptor-mediated calcium influx was still observed in PASMC after CPA pretreatment in the presence of extracellular Ca(2+). Ca(2+) oscillations were triggered by thrombin in PASMC resulting from a balance of extracellular Ca(2+) influx and Ca(2+) reuptake by the sarcoplasmic reticulum. The data show that thrombin induces increases in intracellular calcium in PASMC and PAEC with a distinct CPA-, caffeine-, and ryanodine-insensitive release existing only in PAEC. Furthermore, a dynamic balance between Ca(2+) influx, intracellular Ca(2+) release, and reuptake underlie the Ca(2+) transients evoked by thrombin in some PASMC. Understanding of such mechanisms will provide an important insight into thrombin-mediated vascular injury during hypertension.

Dataset Information

Effect of cocaine on human immunodeficiency virus-mediated pulmonary endothelial and smooth muscle dysfunction.

Publications

Effect of cocaine on human immunodeficiency virus-mediated pulmonary endothelial and smooth muscle dysfunction.

Similar Datasets

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