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; Ladner, Amy O. 'Brien

doi:10.1165/rcmb.2010-0097oc

Cited by 57 publications

(100 citation statements)

References 71 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Similar to our present findings, we earlier reported a potential additive role of HIV infection and cocaine exposure in the development of pulmonary arteriopathy using a pulmonary vascular cell-culture system and archival human lung tissues (11). Furthermore, stimulant use, including amphetamine, methamphetamine, and cocaine, had earlier been reported to be more likely associated in patients with idiopathic PAH (48).…”

Section: Discussionsupporting

confidence: 90%

“…In addition, comparison of two different studies of HIV-infected cohorts from the United States suggests a higher incidence of increased pulmonary arterial systolic pressure in the cohort that had a greater percentage of IVDUs (10). Furthermore, our recent study showing enhanced pulmonary vascular remodeling in HIV-infected lung tissues from IV opioids and/or cocaine abusers (11) indicates that IVDU and HIV-1 potentially act in concert to cause a pulmonary arteriopathy. Although it is clearly evident that HIV-infected patients are at an increased risk for the development of PAH, the mechanisms and the pathogenesis of HIV-PAH remain elusive.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Enhanced Pulmonary Arteriopathy in Simian Immunodeficiency Virus–infected Macaques Exposed to Morphine

Spikes

Dalvi

Tawfik

et al. 2012

Am J Respir Crit Care Med

Self Cite

View full text Add to dashboard Cite

Section: Discussionsupporting

confidence: 90%

mentioning

confidence: 99%

Enhanced Pulmonary Arteriopathy in Simian Immunodeficiency Virus–infected Macaques Exposed to Morphine

Spikes

Dalvi

Tawfik

et al. 2012

Am J Respir Crit Care Med

Self Cite

View full text Add to dashboard Cite

“…Abnormal smooth muscle cell (SMC) proliferation is considered to play a key role in vascular remodeling associated with PAH (17); however, specific mechanisms underlying the drug abuse-and HIV infection-mediated arteriopathy are at their infancy. Our previous findings support an independent effect of cocaine and HIV proteins on the enhancement of pulmonary SMC proliferation (10). Although both abuse of cocaine and HIV proteins have been observed to be an independent risk factor of vascular injury, we reported that the combination of cocaine and HIV protein: transactivator of transcription (Tat) exposure results in a synergistic increase in the proliferation of pulmonary SMCs (10).…”

Section: Human Immunodeficiency Virus (Hiv)-related Pulmonary Arteriasupporting

confidence: 77%

“…A recent report by Quezada and colleagues (3) suggesting 10% prevalence of HRPAH in the Spanish cohort also found association of PAH with intravenous drug use. Previous studies from our laboratory showing enhanced pulmonary vascular remodeling in HIV-infected human lung tissues or simian immunodeficiency virus-infected macaque lungs exposed to intravenous cocaine and/or opioids abuse (10,11) further indicate that intravenous drug use and HIV-1 potentially act in concert to cause pulmonary arteriopathy.…”

Section: Human Immunodeficiency Virus (Hiv)-related Pulmonary Arteriamentioning

confidence: 81%

Ligand-Independent Activation of Platelet-Derived Growth Factor Receptor β during Human Immunodeficiency Virus–Transactivator of Transcription and Cocaine-Mediated Smooth Muscle Hyperplasia

Dalvi¹,

Gupta

Griffin³

et al. 2015

Am J Respir Cell Mol Biol

Self Cite

View full text Add to dashboard Cite

Our previous study supports an additive effect of cocaine to human immunodeficiency virus infection in the development of pulmonary arteriopathy through enhancement of proliferation of pulmonary smooth muscle cells (SMCs), while also suggesting involvement of platelet-derived growth factor receptor (PDGFR) activation in the absence of further increase in PDGF-BB ligand. Redox-related signaling pathways have been shown to regulate tyrosine kinase receptors independent of ligand binding, so we hypothesized that simultaneous treatment of SMCs with transactivator of transcription (Tat) and cocaine may be able to indirectly activate PDGFR through modulation of reactive oxygen species (ROS) without the need for PDGF binding. We found that blocking the binding of ligand using suramin or monoclonal IMC-3G3 antibody significantly reduced ligand-induced autophosphorylation of Y1009 without affecting ligand-independent transphosphorylation of Y934 residue on PDGFRb in human pulmonary arterial SMCs treated with both cocaine and Tat. Combined treatment of human pulmonary arterial SMCs with cocaine and Tat resulted in augmented production of superoxide radicals and hydrogen peroxide when compared with either treatment alone. Inhibition of this ROS generation prevented cocaine-and Tat-mediated Src activation and transphosphorylation of PDGFRb at Y934 without any changes in phosphorylation of Y1009, in addition to attenuation of smooth muscle hyperplasia. Furthermore, pretreatment with an Src inhibitor, PP2, also suppressed cocaine-and Tat-mediated enhanced Y934 phosphorylation and smooth muscle proliferation. Finally, we report total abrogation of cocaine-and Tatmediated synergistic increase in cell proliferation on inhibition of both ligand-dependent and ROS/Src-mediated ligand-independent phosphorylation of PDGFRb.

show abstract

“…This suggests a relationship between heightened signaling via G protein-coupled serotonin and serotonin-like receptors and PAH. There is also evidence of interplay among HIV, cocaine abuse, and heightened activity of PDGF (72).…”

Section: Drugs and Toxinsmentioning

confidence: 99%

Molecular pathogenesis of pulmonary arterial hypertension

Rabinovitch¹

2012

J. Clin. Invest.

691

649

View full text Add to dashboard Cite

Pathological features of PAHPulmonary arterial hypertension (PAH) is diagnosed by an elevation in mean pulmonary arterial (PA) pressure above 25 mmHg at rest or 30 mmHg with exercise. Patients usually present with much higher levels of PA pressure, but only vague and insidious symptoms of increasing fatigue and dyspnea; some patients are diagnosed only after syncopal episodes, which can reflect suprasystemic levels of PA pressure and low cardiac output. The causes of PAH were reclassified according to a consensus at the Fourth World While this review focuses on pulmonary hypertension category 1 (i.e., PAH), pathophysiologic insights can also be gained from understanding other causes of pulmonary hypertension. Hence, experimental studies in hypoxic animals are also discussed.In neonates and in infants, PAH likely results from failure of the neonatal pulmonary vasculature to dilate at birth, and pathological changes in the blood vessels are evident in the first few days of life. Most prominent is abnormal muscularization of distal PAs at the alveolar duct and wall levels and a striking reduction in their number. In older infants and adults, there is also progressive intimal hyperplasia leading to occlusive changes in the PAs and plexiform lesions (Figure 1 and see below).PA EC alterations in the clinical (2) and experimental (3) setting precede muscularization of distal PAs. In PA ECs from patients with idiopathic PAH (IPAH), an increase in Tie2 receptor expression in ECs releases serotonin, mediating SMC proliferation (4). Dysfunctional ECs can either release factors that stimulate SMC proliferation, such as FGF-2 (5), or fail to produce agents that normally suppress proliferation of SMCs in response to growth factors, such as apelin (encoded by Apln) (6).Muscularization of distal, normally nonmuscular, PAs at the alveolar duct and wall level is associated with differentiation of pericytes into SMCs that subsequently proliferate. The progressive thickening of the wall of more proximal intraacinar and preacinar muscular arteries and the obliteration associated with neointimal formation are attributed to increased proliferation and migration of cells considered to be SMCs because they are α-SMA positive (7). The origin of these cells is unclear, and the mechanism of their dysregulation is the subject of intense study. They may represent a specialized subpopulation of SMCs; they may originate as stem cells (8) or fibrocytes (9) or transform from ECs (10, 11). The loss of distal PAs could be caused by alterations in ECs and/or pericytes resulting in apoptosis (12).Later in disease, there is dysregulated EC proliferation, producing aberrant channels in the otherwise obliterated lumen of the vessel and in the adventitia (i.e., the plexiform lesion). These channels may reflect clonal expansion of apoptosis-resistant ECs (13), or they may be derived from circulating endothelial progenitor cells (EPCs) that accumulate at sites of endothelial denudation or injury and expand locally (14). PA ECs from patients with IPAH prod...

show abstract

Effect of Cocaine on Human Immunodeficiency Virus–Mediated Pulmonary Endothelial and Smooth Muscle Dysfunction

Cited by 57 publications

References 71 publications

Enhanced Pulmonary Arteriopathy in Simian Immunodeficiency Virus–infected Macaques Exposed to Morphine

Enhanced Pulmonary Arteriopathy in Simian Immunodeficiency Virus–infected Macaques Exposed to Morphine

Ligand-Independent Activation of Platelet-Derived Growth Factor Receptor β during Human Immunodeficiency Virus–Transactivator of Transcription and Cocaine-Mediated Smooth Muscle Hyperplasia

Molecular pathogenesis of pulmonary arterial hypertension

Contact Info

Product

Resources

About