41 research outputs found
Extracellular vesicles: Novel communicators in lung diseases
This work is licensed under a Creative Commons Attribution 4.0 International License.The lung is the organ with the highest vascular density in the human body. It is therefore perceivable that the endothelium of the lung contributes significantly to the circulation of extracellular vesicles (EVs), which include exosomes, microvesicles, and apoptotic bodies. In addition to the endothelium, EVs may arise from alveolar macrophages, fibroblasts and epithelial cells. Because EVs harbor cargo molecules, such as miRNA, mRNA, and proteins, these intercellular communicators provide important insight into the health and disease condition of donor cells and may serve as useful biomarkers of lung disease processes. This comprehensive review focuses on what is currently known about the role of EVs as markers and mediators of lung pathologies including COPD, pulmonary hypertension, asthma, lung cancer and ALI/ARDS. We also explore the role EVs can potentially serve as therapeutics for these lung diseases when released from healthy progenitor cells, such as mesenchymal stem cells.NiH R01DA042715NIH R01HL129875NIH P20 GM10363
Hypoxia-inducible factor-1 α/platelet derived growth factor axis in HIV-associated pulmonary vascular remodeling
<p>Abstract</p> <p>Background</p> <p>Human immunodeficiency virus (HIV) infected patients are at increased risk for the development of pulmonary arterial hypertension (PAH). Recent reports have demonstrated that HIV associated viral proteins induce reactive oxygen species (ROS) with resultant endothelial cell dysfunction and related vascular injury. In this study, we explored the impact of HIV protein induced oxidative stress on production of hypoxia inducible factor (HIF)-1α and platelet-derived growth factor (PDGF), critical mediators implicated in the pathogenesis of HIV-PAH.</p> <p>Methods</p> <p>The lungs from 4-5 months old HIV-1 transgenic (Tg) rats were assessed for the presence of pulmonary vascular remodeling and HIF-1α/PDGF-BB expression in comparison with wild type controls. Human primary pulmonary arterial endothelial cells (HPAEC) were treated with HIV-associated proteins in the presence or absence of pretreatment with antioxidants, for 24 hrs followed by estimation of ROS levels and western blot analysis of HIF-1α or PDGF-BB.</p> <p>Results</p> <p>HIV-Tg rats, a model with marked viral protein induced vascular oxidative stress in the absence of active HIV-1 replication demonstrated significant medial thickening of pulmonary vessels and increased right ventricular mass compared to wild-type controls, with increased expression of HIF-1α and PDGF-BB in HIV-Tg rats. The up-regulation of both HIF-1α and PDGF-B chain mRNA in each HIV-Tg rat was directly correlated with an increase in right ventricular/left ventricular+septum ratio. Supporting our <it>in-viv</it>o findings, HPAECs treated with HIV-proteins: Tat and gp120, demonstrated increased ROS and parallel increase of PDGF-BB expression with the maximum induction observed on treatment with R5 type gp-120<sub>CM</sub>. Pre-treatment of endothelial cells with antioxidants or transfection of cells with HIF-1α small interfering RNA resulted in abrogation of gp-120<sub>CM </sub>mediated induction of PDGF-BB, therefore, confirming that ROS generation and activation of HIF-1α plays critical role in gp120 mediated up-regulation of PDGF-BB.</p> <p>Conclusion</p> <p>In summary, these findings indicate that viral protein induced oxidative stress results in HIF-1α dependent up-regulation of PDGF-BB and suggests the possible involvement of this pathway in the development of HIV-PAH.</p
Impact of human immunodeficiency virus on pulmonary vascular disease
With the advent of anti-retroviral therapy, non-AIDS-related comorbidities have increased in people living with HIV. Among these comorbidities, pulmonary hypertension (PH) is one of the most common causes of morbidity and mortality. Although chronic HIV-1 infection is independently associated with the development of pulmonary arterial hypertension, PH in people living with HIV may also be the outcome of various co-morbidities commonly observed in these individuals including chronic obstructive pulmonary disease, left heart disease and co-infections. In addition, the association of these co-morbidities and other risk factors, such as illicit drug use, can exacerbate the development of pulmonary vascular disease. This review will focus on these complex interactions contributing to PH development and exacerbation in HIV patients. We also examine the interactions of HIV proteins, including Nef, Tat, and gp120 in the pulmonary vasculature and how these proteins alter the endothelial and smooth muscle function by transforming them into susceptible PH phenotype. The review also discusses the available infectious and non-infectious animal models to study HIV-associated PAH, highlighting the advantages and disadvantages of each model, along with their ability to mimic the clinical manifestations of HIV-PAH
HIV-Nef Protein Persists in the Lungs of Aviremic Patients with HIV and Induces Endothelial Cell Death
It remains a mystery why HIV-associated end-organ pathologies persist in the era of combined antiretroviral therapy (ART). One possible mechanism is the continued production of HIV-encoded proteins in latently HIV-infected T cells and macrophages. The proapoptotic protein HIV-Nef persists in the blood of ART-treated patients within extracellular vesicles (EVs) and peripheral blood mononuclear cells. Here we demonstrate that HIV-Nef is present in cells and EVs isolated from BAL of patients on ART. We hypothesize that HIV-Nef persistence in the lung induces endothelial apoptosis leading to endothelial dysfunction and further pulmonary vascular pathologies. The presence of HIV-Nef in patients with HIV correlates with the surface expression of the proapoptotic endothelial-monocyte–activating polypeptide II (EMAPII), which was implicated in progression of pulmonary emphysema via mechanisms involving endothelial cell death. HIV-Nef protein induces EMAPII surface expression in human embryonic kidney 293T cells, T cells, and human and mouse lung endothelial cells. HIV-Nef packages itself into EVs and increases the amount of EVs secreted from Nef-expressing T cells and Nef-transfected human embryonic kidney 293T cells. EVs from BAL of HIV+ patients and Nef-transfected cells induce apoptosis in lung microvascular endothelial cells by upregulating EMAPII surface expression in a PAK2-dependent fashion. Transgenic expression of HIV-Nef in vascular endothelial–cadherin+ endothelial cells leads to lung rarefaction, characterized by reduced alveoli and overall increase in lung inspiratory capacity. These changes occur concomitantly with lung endothelial cell apoptosis. Together, these data suggest that HIV-Nef induces endothelial cell apoptosis via an EMAPII-dependent mechanism that is sufficient to cause pulmonary vascular pathologies even in the absence of inflammation
HIV-1 Tat Co-Operates with IFN-γ and TNF-α to Increase CXCL10 in Human Astrocytes
HIV-associated neurological disorders (HAND) are estimated to affect 60% of the HIV infected population. HIV-encephalitis (HIVE), the pathological correlate of the most severe form of HAND is often characterized by glial activation, cytokine/chemokine dysregulation, and neuronal damage and loss. However, the severity of HIVE correlates better with glial activation rather than viral load. One of the characteristic features of HIVE is the increased amount of the neurotoxic chemokine, CXCL10. This chemokine can be released from astroglia activated with the pro-inflammatory cytokines IFN-γ and TNF-α, in conjunction with HIV-1 Tat, all of which are elevated in HIVE. In an effort to understand the pathogenesis of HAND, this study was aimed at exploring the regulation of CXCL10 by cellular and viral factors during astrocyte activation. Specifically, the data herein demonstrate that the combined actions of HIV-1 Tat and the pro-inflammatory cytokines, IFN-γ and TNF-α, result in the induction of CXCL10 at both the RNA and protein level. Furthermore, CXCL10 induction was found to be regulated transcriptionally by the activation of the p38, Jnk, and Akt signaling pathways and their downstream transcription factors, NF-κB and STAT-1α. Since CXCL10 levels are linked to disease severity, understanding its regulation could aid in the development of therapeutic intervention strategies for HAND
Potential long-term effects of SARS-CoV-2 infection on the pulmonary vasculature: Multilayered cross-talks in the setting of coinfections and comorbidities
The Coronavirus Disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and its sublineages pose a new challenge to healthcare systems worldwide due to its ability to efficiently spread in immunized populations and its resistance to currently available therapies. COVID-19, although targeting primarily the respiratory system, is also now well established that later affects every organ in the body. Most importantly, despite the available therapy and vaccine-elicited protection, the long-term consequences of viral infection in breakthrough and asymptomatic individuals are areas of concern. In the past two years, investigators accumulated evidence on how the virus triggers our immune system and the molecular signals involved in the cross-talk between immune cells and structural cells in the pulmonary vasculature to drive pathological lung complications such as endothelial dysfunction and thrombosis. In the review, we emphasize recent updates on the pathophysiological inflammatory and immune responses associated with SARS-CoV-2 infection and their potential long-term consequences that may consequently lead to the development of pulmonary vascular diseases
Exploring extracellular vesicles as mediators of clinical disease and vehicles for viral therapeutics: Insights from the COVID-19 pandemic
The COVID-19 pandemic has challenged researchers to rapidly understand the capabilities of the SARS-CoV-2 virus and investigate potential therapeutics for SARS-CoV-2 infection. COVID-19 has been associated with devastating lung and cardiac injury, profound inflammation, and a heightened coagulopathic state, which may, in part, be driven by cellular crosstalk facilitated by extracellular vesicles (EVs). In recent years, EVs have emerged as important biomarkers of disease, and while extracellular vesicles may contribute to the spread of COVID-19 infection from one cell to the next, they also may be engineered to play a protective or therapeutic role as decoys or “delivery drivers” for therapeutic agents. This review explores these roles and areas for future study
Drug abuse and HIV-related pulmonary hypertension: double hit injury
: Improved survival among HIV-1-infected individuals with the advent of antiretroviral therapy has clearly led to a greater prevalence of noninfectious complications. One of the most devastating sequelae in these individuals is the development of pulmonary arterial hypertension (PAH). Various epidemiological studies suggest worse survival of HIV-PAH patients when compared with other forms of PAH. Given that only a subset and not all HIV-infected individuals develop HIV-PAH, it is suggested that an additional second-hit of genetic or environmental trigger is needed for the development of PAH. In this context, it has been well documented that HIV patients who abuse illicit drugs such as stimulants, opioids, and the like, are more susceptible to develop PAH. In this review, we highlight the studies that support the significance of a double hit of HIV and drug abuse in the incidence of PAH and focus on the research that has been undertaken to unravel the pathobiology and vascular remodeling mechanisms underlying the deleterious synergy between HIV infection and drugs of abuse in orchestrating the development of PAH
Potential long-term effects of SARS-CoV-2 infection on the pulmonary vasculature: Multilayered cross-talks in the setting of coinfections and comorbidities
The Coronavirus Disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and its sublineages pose a new challenge to healthcare systems worldwide due to its ability to efficiently spread in immunized populations and its resistance to currently available therapies. COVID-19, although targeting primarily the respiratory system, is also now well established that later affects every organ in the body. Most importantly, despite the available therapy and vaccine-elicited protection, the long-term consequences of viral infection in breakthrough and asymptomatic individuals are areas of concern. In the past two years, investigators accumulated evidence on how the virus triggers our immune system and the molecular signals involved in the cross-talk between immune cells and structural cells in the pulmonary vasculature to drive pathological lung complications such as endothelial dysfunction and thrombosis. In the review, we emphasize recent updates on the pathophysiological inflammatory and immune responses associated with SARS-CoV-2 infection and their potential long-term consequences that may consequently lead to the development of pulmonary vascular diseases.Depto. de Farmacología y ToxicologíaFac. de MedicinaTRUEpu