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

Navneet K. Dhillon, Fang Li, Bing Xue, Ossama Tawfik, Susan Morgello, Shilpa J Buch, Amy O Brien Ladner

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Human immunodeficiency virus (HIV)-associated pulmonary arterial hypertension (PAH) is a devastating, noninfectious complication of acquired immune deficiency syndrome, and the majority of HIVPAH 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 plateletderived 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, andthe proliferation of pulmonarysmooth 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.

Original languageEnglish (US)
Pages (from-to)40-52
Number of pages13
JournalAmerican journal of respiratory cell and molecular biology
Volume45
Issue number1
DOIs
StatePublished - Jul 1 2011

Fingerprint

Cocaine
Viruses
Smooth Muscle
Muscle
HIV
Lung
Pulmonary Hypertension
Trans-Activators
Muscle Cells
Tight Junction Proteins
Transcription
Intercellular Signaling Peptides and Proteins
Pharmaceutical Preparations
Growth Factor Receptors
Endothelial cells
HIV-1
Endothelial Cells
Virus Diseases
Small Interfering RNA
Macrophages

Keywords

  • Platelet-derived growth factor
  • Tight junction proteins
  • Trans-activator of transcription
  • Vascular remodeling

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

Cite this

Effect of cocaine on human immunodeficiency virus-mediated pulmonary endothelial and smooth muscle dysfunction. / Dhillon, Navneet K.; Li, Fang; Xue, Bing; Tawfik, Ossama; Morgello, Susan; Buch, Shilpa J; Ladner, Amy O Brien.

In: American journal of respiratory cell and molecular biology, Vol. 45, No. 1, 01.07.2011, p. 40-52.

Research output: Contribution to journalArticle

Dhillon, Navneet K. ; Li, Fang ; Xue, Bing ; Tawfik, Ossama ; Morgello, Susan ; Buch, Shilpa J ; Ladner, Amy O Brien. / Effect of cocaine on human immunodeficiency virus-mediated pulmonary endothelial and smooth muscle dysfunction. In: American journal of respiratory cell and molecular biology. 2011 ; Vol. 45, No. 1. pp. 40-52.
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