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

Spikes, Leslie; Dalvi, Pranjali; Tawfik, Ossama; Gu, Haihua; Voelkel, Norbert F.; Cheney, Paul D.; O’Brien-Ladner, Amy; Dhillon, Navneet K.

doi:10.1164/rccm.201110-1909oc

Cited by 61 publications

(100 citation statements)

References 52 publications

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“…Hepatitis B virus stabilizes hypoxia-inducible factor a and leads to the downstream development of PH in vitro (6,28). More recently, Spikes and colleagues demonstrated macaques infected with SIV and injected with morphine have markedly increased pulmonary vascular changes, with increased numbers of apoptosisresistant cells and advanced plexiform lesions, when compared with morphinetreated, uninfected animals or SIV-infected animals (14). Although in our study IDU was not associated with PASP or PH, it is unknown whether in humans HCV adds another "hit" to the pulmonary vasculature by acting synergistically with injection drugs and/or HIV infection, especially because HIV-HCV coinfection is frequently transmitted via IDU (15,29).…”

Section: Original Researchmentioning

confidence: 99%

“…It is possible that chronic HCV infection is an independent risk factor for PH but also that the risk of PH with HIV-HCV coinfection is additive. Intravenous morphine exposure and simian immunodeficiency virus (SIV) act synergistically to promote pulmonary vasculopathy in macaques (14). Injection drug use (IDU) is the most common mode of HCV transmission in the United States, and HIV-HCV coinfection rates among patients with IDU are greater than 50% (15,16).…”

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confidence: 99%

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Risk of Echocardiographic Pulmonary Hypertension in Individuals with Human Immunodeficiency Virus–Hepatitis C Virus Coinfection

et al. 2014

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Rationale: Human immunodeficiency virus (HIV) infection is a risk factor for pulmonary hypertension (PH). Chronic hepatitis C virus (HCV) infection may have unique or synergistic effects on the pulmonary vasculature, but the prevalence and risk factors for PH in HIV-HCV coinfected persons are not known.Objectives: To define the prevalence of echocardiographic PH in a cohort of patients with HIV-HCV coinfection, to compare this estimate with the reported prevalence of PH among those with HIV infection alone, and to identify potential risk factors for PH in coinfected individuals.Methods: We performed a retrospective study of HIV-HCV coinfected patients followed at our institution from 2003 to 2012 with evidence of HCV infection (positive HCV antibody, measurable HCV ribonucleic acid viral load, and/or genotype) within 6 months of transthoracic echocardiogram. PH was defined by an estimated pulmonary artery systolic pressure (PASP) of greater than or equal to 40 mm Hg or more than moderate right ventricular dysfunction. We excluded those diagnosed with cirrhosis, left ventricular ejection fraction less than 50%, or more than moderate aortic or mitral valve disease. Measurements and Main Results:Sixty-eight patients were included, and 43 had adequate estimates of PASP. The median (interquartile range) age was 52 (48-57) years, and 45 (67%) were men. Eight (19%) had PH, and three (7%) had more than moderate right ventricular dysfunction. After age and sex adjustment, interferon (IFN)-based HCV treatment was associated with higher PASP (b, 6.00 mm Hg; 95% confidence interval, 0.09-11.90; P = 0.047) and with the risk of PH (odds ratio, 5.65; 95% confidence interval, 1.07-29.93; P = 0.042). These associations persisted after adjustment for comorbidities but were attenuated by adjustment for duration of HCV diagnosis. Conclusions:The prevalence of echocardiographic PH may be higher in HIV-HCV coinfected individuals than in those with HIV monoinfection. IFN-based HCV treatment and time since HCV diagnosis were associated with the development of PH as assessed by echocardiography. Further studies are needed to examine HIV-HCV coinfection, HCV treatment, and duration of infection as possible causes of pulmonary vascular disease.

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Section: Original Researchmentioning

confidence: 99%

mentioning

confidence: 99%

Risk of Echocardiographic Pulmonary Hypertension in Individuals with Human Immunodeficiency Virus–Hepatitis C Virus Coinfection

et al. 2014

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“…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: 80%

“…One of the key mediators in ligandindependent transactivation of growth factor receptors, including PDGFR, are reactive oxygen species (ROS) (24). We and others have demonstrated induction of oxidative stress on exposure of vascular cell types to various HIV proteins, including Tat, and on exposure to illicit drugs, such as cocaine and opioids (11,25,26). Therefore, in this study, we explored the possibility of ROS-mediated ligand-independent activation of PDGFR in HPASMCs on combined treatment with cocaine and Tat.…”

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

confidence: 99%

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

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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.

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“…1235-1243) study a nonhuman primate model to investigate the effect of morphine on simian immunodeficiency virus (SIV) infection and the development of pulmonary hypertension (6). They report that rhesus macaques pretreated with morphine for 26 weeks, followed by inoculation with macrophage-tropic SIVmacR71/17E virus, and subsequent treatment with intramuscular morphine for 31 weeks after inoculation, develop significant pulmonary vascular remodeling including plexiform lesions, whereas animals either infected with SIV alone or treated with morphine alone did not.…”

mentioning

confidence: 99%

Injection Drug Use as a “Second Hit” in the Pathogenesis of HIV-associated Pulmonary Hypertension

George

Champion

Gladwin

et al. 2012

Am J Respir Crit Care Med

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

Cited by 61 publications

References 52 publications

Risk of Echocardiographic Pulmonary Hypertension in Individuals with Human Immunodeficiency Virus–Hepatitis C Virus Coinfection

Risk of Echocardiographic Pulmonary Hypertension in Individuals with Human Immunodeficiency Virus–Hepatitis C Virus Coinfection

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

Injection Drug Use as a “Second Hit” in the Pathogenesis of HIV-associated Pulmonary Hypertension

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