Rosiglitazone attenuates chronic hypoxia-induced pulmonary hypertension in a mouse model.

Chronic hypoxia contributes to pulmonary hypertension through complex mechanisms that include enhanced NADPH oxidase expression and reactive oxygen species (ROS) generation in the lung. Stimulation of peroxisome proliferator-activated receptor gamma (PPARgamma) reduces the expression and activity of NADPH oxidase. Therefore, we hypothesized that activating PPARgamma with rosiglitazone would attenuate chronic hypoxia-induced pulmonary hypertension, in part, through suppressing NADPH oxidase-derived ROS that stimulate proliferative signaling pathways. Male C57Bl/6 mice were exposed to chronic hypoxia (CH, Fi(O2) 10%) or room air for 3 or 5 weeks. During the last 10 days of exposure, each animal was treated daily by gavage with either the PPARgamma ligand, rosiglitazone (10 mg/kg/d) or with an equal volume of vehicle. CH increased: (1) right ventricular systolic pressure (RVSP), (2) right ventricle weight, (3) thickness of the walls of small pulmonary vessels, (4) superoxide production and Nox4 expression in the lung, and (5) platelet-derived growth factor receptor beta (PDGFRbeta) expression and activity and reduced phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression. Treatment with rosiglitazone prevented the development of pulmonary hypertension at 3 weeks; reversed established pulmonary hypertension at 5 weeks; and attenuated CH-stimulated Nox4 expression and superoxide production, PDGFRbeta activation, and reductions in PTEN expression. Rosiglitazone also attenuated hypoxia-induced increases in Nox4 expression in pulmonary endothelial cells in vitro despite hypoxia-induced reductions in PPARgamma expression. Collectively, these findings indicate that PPARgamma ligands attenuated hypoxia-induced pulmonary vascular remodeling and hypertension by suppressing oxidative and proliferative signals providing novel insights for mechanisms underlying therapeutic effects of PPARgamma activation in pulmonary hypertension.

The role of NADPH oxidase in chronic intermittent hypoxia-induced pulmonary hypertension in mice.

Obstructive sleep apnea, characterized by intermittent periods of hypoxemia, is an independent risk factor for the development of pulmonary hypertension. However, the exact mechanisms of this disorder remain to be defined. Enhanced NADPH oxidase expression and superoxide (O2(-).) generation in the pulmonary vasculature play a critical role in hypoxia-induced pulmonary hypertension. Therefore, the current study explores the hypothesis that chronic intermittent hypoxia (CIH) causes pulmonary hypertension, in part, by increasing NADPH oxidase-derived reactive oxygen species (ROS) that contribute to pulmonary vascular remodeling and hypertension. To test this hypothesis, male C57Bl/6 mice and gp91phox knockout mice were exposed to CIH for 8 hours per day, 5 days per week for 8 weeks. CIH mice were placed in a chamber where the oxygen concentration was cycled between 21% and 10% O2 45 times per hour. Exposure to CIH for 8 weeks increased right ventricular systolic pressure (RVSP), right ventricle (RV):left ventricle (LV) + septum (S) weight ratio, an index of RV hypertrophy, and thickness of the right ventricular anterior wall as measured by echocardiography. CIH exposure also caused pulmonary vascular remodeling as demonstrated by increased muscularization of the distal pulmonary vasculature. CIH-induced pulmonary hypertension was associated with increased lung levels of the NADPH oxidase subunits, Nox4 and p22phox, as well as increased activity of platelet-derived growth factor receptor beta and its associated downstream effector, Akt kinase. These CIH-induced derangements were attenuated in similarly treated gp91phox knockout mice. These findings demonstrate that NADPH oxidase-derived ROS contribute to the development of pulmonary vascular remodeling and hypertension caused by CIH.

The role of peroxisome proliferator-activated receptors in pulmonary vascular disease.

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear hormone receptor superfamily that regulate diverse physiological processes ranging from lipogenesis to inflammation. Recent evidence has established potential roles of PPARs in both systemic and pulmonary vascular disease and function. Existing treatment strategies for pulmonary hypertension, the most common manifestation of pulmonary vascular disease, are limited by an incomplete understanding of the underlying disease pathogenesis and lack of efficacy indicating an urgent need for new approaches to treat this disorder. Derangements in pulmonary endothelial-derived mediators and endothelial dysfunction have been shown to play a pivotal role in pulmonary hypertension pathogenesis. Therefore, the following review will focus on selected mediators implicated in pulmonary vascular dysfunction and evidence that PPARs, in particular PPARgamma, participate in their regulation and may provide a potential novel therapeutic target for the treatment of pulmonary hypertension.

The role of infection and comorbidity: Factors that influence disparities in sepsis.

OBJECTIVE: Large healthcare disparities exist in the incidence of sepsis based on both race and gender. We sought to determine factors that may influence the occurrence of these healthcare disparities, with respect to the source of infection, causal organisms, and chronic comorbid medical conditions. DESIGN: Historical cohort study. SETTING: U.S. acute care hospitals from 1979 to 2003. PATIENTS: Hospitalized patients with a diagnosis of sepsis were identified from the National Hospital Discharge Survey per codes of the International Statistical Classification of Diseases, Ninth Revision (ICD-9CM). Chronic comorbid medical conditions and the source and type of infection were characterized by corresponding ICD-9CM diagnoses. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Sepsis incidence rates are mean cases per 100,000 after age adjustment to the 2000 U.S. Census. Males and nonwhite races were confirmed at increased risk for sepsis. Both proportional source distribution and incidence rates favored respiratory sources of sepsis in males (36% vs. 29%, p < .01) and genitourinary sources in females (35% vs. 27%, p < .01). Incidence rates for all common sources of sepsis were greater in nonwhite races, but proportional source distribution was approximately equal. After stratification by the source of infection, males (proportionate ratio 1.16, 95% confidence interval 1.04-1.29) and black persons (proportionate ratio 1.25, 95% confidence interval 1.18-1.32) remained more likely to have Gram-positive infections. Chronic comorbid conditions that alter immune function (chronic renal failure, diabetes mellitus, HIV, alcohol abuse) were more common in nonwhite sepsis patients, and cumulative comorbidities were associated with greater acute organ dysfunction. Compared with white sepsis patients, nonwhite sepsis patients had longer hospital length of stay (2.0 days, 95% confidence interval 1.9-2.1) and were less likely to be discharged to another medical facility (30% whites, 25% blacks, 18% other races). Case-fatality rates were not significantly different across racial and gender groups. CONCLUSIONS: Healthcare disparities exist in the incidence of sepsis within all major sources of infection, and males and blacks have greater frequency of Gram-positive infections independent of the infection source. The differential distribution of specific chronic comorbid medical conditions may contribute to these disparities. Large cohort and administrative studies are required to confirm discrete root causes of sepsis disparities.