Highly Active Antiretroviral Therapy (HAART) Leads to Pulmonary Hypertension
Researchers led by Dr. Changyi Chen at Baylor College of Medicine discovered that HAART contributes to pulmonary hypertension in HIV-infected patients. This report can be found in the March 2009 issue of The American Journal of Pathology.
An estimated 33 million people were living with human immunodeficiency virus (HIV infection) in 2007. Without treatment, approximately 9 out of 10 HIV-infected people will progress to acquired immune deficiency syndrome (AIDS) with 5-10 years.
HAART is a combination therapy for HIV that consists of at least three antiretroviral drugs that suppress viral replication and restore CD4+ T cell numbers in HIV-infected patients. HAART dramatically improves the prognosis of HIV-infected patients; however, HAART drugs may increase the risk of cardiovascular disease.
Wang et al hypothesized that HAART drugs contribute to the risk for cardiovascular disease by impairing blood vessel-lining endothelial cell function. Their studies demonstrated that treatment of porcine pulmonary arteries with HAART drugs individually and in combination resulted in functional deficiencies in endothelial cells lining the blood vessels of the lungs. Therefore, HAART drugs may play a role in the high incidence of pulmonary artery hypertension in HIV-infected patients.
The research by Dr. Chen's group "showed that several HAART drugs including ritonavir, indinavir, lamivudine, abacavir and AZT can cause endothelial dysfunction through decreasing eNOS expression and increasing oxidative stress in porcine pulmonary arteries and [human pulmonary artery endothelial cells]. Consequently, reducing oxidative stress by selected antioxidants may be able to prevent HAART drugs-associated pulmonary artery hypertension."
Wang, X, Chai H, Lin PH, Yao Q, Chen C: Roles and mechanisms of HIV protease inhibitor Ritonavir and other anti-HIV drugs in endothelial dysfunction of porcine pulmonary arteries and human pulmonary artery endothelial cells. Am J Pathol 2009, 174: 771-781
Novel Treatment for Chronic Hypoxic Pulmonary Hypertension (PHTN)
Dr. Edward Dempsey and colleagues of the University of Colorado observed that neprilysin protects against PHTN. They present their data in the March 2009 issue of The American Journal of Pathology.
Patients with pulmonary hypertension, an increase in pressure in blood vessels in the lung, may exhibit shortness of breath, dizziness, or fainting, especially while exercising. Hypoxic pulmonary hypertension is caused by lack of oxygen, often due to other lung or heart disorders. One complicating factor in PHTN is vascular remodeling, where the blood vessels of the lung and the muscles surrounding them are permanently altered by the hypertension.
Neprilysin is a protein that is expressed within the blood vessels of the lung. Neprilysin breaks down neural signaling molecules that regulate both growth and contraction of the muscle cells around the blood vessels. To determine if depletion of neprilysin increased susceptibility to PHTN in response to chronic hypoxia, Dempsey et al generated a mouse model deficient in neprilysin. Although neprilysin deficiency had minimal effects on baseline cardiac and pulmonary function, upon hypoxic exposure, neprilysin-deficient mice had an augmented pulmonary hypertensive response. In addition, Dempsey et al observed increased proliferation of pulmonary smooth muscle cells in these mice, which was reduced upon reintroduction of neprilysin. Thus, introduction of neprilysin into the lungs of PHTN patients may provide a novel treatment for PHTN.
The neprilysin deficient mouse model of PHTN created by Dempsey et al demonstrates "changes in the pulmonary vasculature … , which are similar to those found in large animal models of hypoxic PHTN that closely parallel human disease and are usually not associated with mouse models of chronic hypoxic PHTN. [Demsey et al] believe that further work with the [neprilysin deficient] mouse model of chronic hypoxic PHTN may lead to the identification of new therapeutic strategies or targets to limit or reverse this important clinical problem."
Dempsey EC, Wick MJ, Karoor V, Barr EJ, Tallman DW, Wehling CA, Walchak SJ, Laudi S, Le M, Oka M, Majka S, Cool CD, Fagan KA, Klemm DJ, Hersh LB, Gerard NP, Gerard C, Miller YE: Neprilysin null mice develop exaggerated pulmonary vascular remodeling in response to chronic hypoxia. Am J Pathol 2009, 174: 782-796
Dividing Cells May Contribute to Alzheimer's Disease
Dr. Mark Smith and colleagues at Case Western Reserve University found that dysregulated cell cycle control may contribute to neural cell death. They report their findings in the March 2009 issue of The American Journal of Pathology.
Neurodegeneration consists of the progressive loss of structure or function of neurons, often resulting in neural cell death. The causes of cell death in neurodegenerative diseases such as Alzheimer's and Parkinson's are incompletely understood. Mature neurons in healthy individuals do not divide; however, degenerating neurons express a protein, c-Myc (Myc), which regulates cell division.
Lee et al therefore explored the role of re-entry into the cell cycle, leading to cell division, in the neurodegenerative pathogenesis. They found that expression of Myc in forebrain neurons resulted in cell cycle re-entry. Furthermore, Myc expression resulted in neural cell death and cognitive defects. Neurodegeneration, therefore, may be a disease of dysregulated cell-cycle control, and cell-cycle regulators should be explored as future treatment targets.
Dr. Lee and colleagues "strengthen [their] hypothesis that neurodegeneration in [Alzheimer's disease], like cellular proliferation in cancer, is a disease of inappropriate cell cycle control." They "establish a model [that] provides a working platform to test genetic and pharmacologic approaches to block cycle re-entry" and thus explore new methods of treating neurodegenerative diseases.
Lee H-G, Casadesus G, Nunomura A, Castellani RJ, Richardson SL, Perry G, Felsher DW, Petersen RB, Smith MA: The neuronal expression of MYC causes a neurodegenerative phenotype in a novel transgenic mouse. Am J Pathol 2009, 174: 891-897
A Vaccine for the Plague
A group led by Dr. Olaf Schneewind at The University of Chicago has proposed Brown Norway rats as a new model for plague vaccine development. They report these findings in the March 2009 issue of The American Journal of Pathology.
Pneumonic plague is the most virulent form of infection caused by Yersinia pestis. Unlike bubonic plague, pneumonic plaque can be transmitted from person to person, and pneumonic plague is often fatal if treatment is not initiated within twelve hours of fever onset. There is currently no licensed vaccine for plague. Given the recent increase in multi-drug resistant microbes, it is imperative to develop a vaccine for plague.
Multiple animal models must be used to evaluate the efficacy of plague vaccines because human clinical trials that test new vaccines are not feasible. Anderson et al propose using Brown Norway rats as an alternate model to mice for studying plague vaccine performance because of their larger size and epidemiological association with Y. pestis infection. These rats succumb to pneumonic plague rapidly, within two to four days, with similar disease progression as in humans. Brown Norway rats could be protected from disease by vaccination with either the protective antigen LcrV or its mutant derivative V10. These results validate the use of Brown Norway rats to study plague pathogenesis and immunity.
Dr. Schneewind and colleagues "focused ... on the Brown Norway rat due to close similarities between rat and human bubonic plague. [They] describe the Brown Norway rat as a model for pneumonic plague and its use in the evaluation of LcrV plague vaccines."
Anderson DM, Ciletti, NA, Lee-Lewis H, Elli D, Segal J, DeBord KL, Overheim KA, Tretiakova M, Brubaker RR, Schneewind O: Pneumonic plague pathogenesis and immunity in Brown Norway rats. Am J Pathol 2009, 174: 910-921
Hemorrhage-Associated Macrophages (HA-mac) Protect Against Atherosclerosis
Researchers at Imperial College London found a novel population of macrophages in hemorrhaged atherosclerotic plaques that protect against atherosclerosis. These findings are presented in the March 2009 issue of The American Journal of Pathology.
Cardiovascular disease is the number one cause of death and disability in the United States. Atherosclerosis, or disease of the arteries, is caused by the build-up of hardened plaques along the arterial wall, decreasing the diameter of the arteries and increasing blood pressure.
White blood cells, including macrophages, are thought to contribute to atherosclerosis through the secretion of pro-inflammatory molecules. Plaque hemorrhage promotes progression and clinical symptoms of cardiovascular disease; however, macrophages found in hemorrhaged atherosclerotic plaques secrete the atheroprotective molecule IL-10.
Dr. Joseph Boyle and colleagues examined the macrophage phenotype in hemorrhaged atherosclerotic plaques and found a novel population of macrophages, HA-macs, which expressed high levels of a molecule that binds the hemoglobin in blood. These HA-macs caused less damage and produced lower levels of inflammatory molecules than conventional pro-atherogenic macrophages. In addition, macrophages develop into HA-macs in the presence of anti-inflammatory molecules, such as IL-10. Skewing macrophage differentiation to atheroprotective HA-mac may comprise a new cardio-protective therapeutic strategy.
This work "predict[s] that HA-mac would suppress the impact of hemorrhage on atherosclerosis progression. In culprit lesions, the effects of HA-mac are by definition too little and too late, but therapeutic modification of HA-mac pathways may prevent plaque destabilization."
Boyle JJ, Harrington HA, Piper E, Elderfield K, Stark J, Landis RC, Haskard DO: Coronary interplaque hemorrhage evokes a novel atheroprotective macrophage phenotype. Am J Pathol 2009, 174: 1097-1108
For press copies of these articles, please contact Dr. Angela Colmone at 301-634-7953 or email@example.com.
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