Free hemoglobin induction of pulmonary vascular disease: Evidence for an inflammatory mechanism

Laboratory of Biochemistry and Vascular Biology, Office of Blood Research and Review, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Bethesda, MD, USA.
AJP Lung Cellular and Molecular Physiology (Impact Factor: 4.08). 06/2012; 303(4):L312-26. DOI: 10.1152/ajplung.00074.2012
Source: PubMed


Cell-free hemoglobin (Hb) exposure may be a pathogenic mediator in the development of pulmonary arterial hypertension (PAH), and when combined with chronic hypoxia the potential for exacerbation of PAH and vascular remodeling is likely more pronounced. We hypothesized that Hb may contribute to hypoxia-driven PAH collectively as a prooxidant, inflammatory, and nitric oxide (NO) scavenger. Using programmable micropump technology, we exposed male Sprague-Dawley rats housed under room air or hypoxia to 12 or 30 mg per day Hb for 3, 5, and 7 wk. Blood pressure, cardiac output, right ventricular hypertrophy, and indexes of pulmonary vascular remodeling were evaluated. Additionally, markers of oxidative stress, NO bioavailability and inflammation were determined. Hb increased pulmonary arterial (PA) pressure, pulmonary vessel wall stiffening, and right heart hypertrophy with temporal and dose dependence in both room air and hypoxic cohorts. Hb induced a modest increase in plasma oxidative stress markers (malondialdehyde and 4-hydroxynonenal), no change in NO bioavailability, and increased lung ICAM protein expression. Treatment with the antioxidant Tempol attenuated Hb-induced pulmonary arterial wall thickening, but not PA pressures or ICAM expression. Chronic exposure to low plasma Hb concentrations (range = 3-10 μM) lasting up to 7 wk in rodents induces pulmonary vascular disease via inflammation and to a lesser extent by Hb-mediated oxidation. Tempol demonstrated a modest effect on the attenuation of Hb-induced pulmonary vascular disease. NO bioavailability was found to be of minimal importance in this model.

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Available from: Kurt Stenmark, Jan 02, 2016
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    • "iPRECIO pumps were programmed to deliver Hb at a dose of 35 mg/day or 250 μg/ml or saline at an infusion rate of 6 μl per hour and were refilled with fresh aliquots of Hb every 3 days for 5 weeks. At an infusion rate of 35 mg/day, we have previously shown that total plasma heme concentrations were in a close range of values that approximate a mild to moderate chronic hemolytic state [9] [21]. All animals tolerated the surgical procedure for pump implantation well, without any fatalities, and wounds were healed within 10 days of the procedure in all animals. "

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    • "Rats were anesthetized with ketamine/xylazine (80 mg/kg/8 mg/kg), and placed in lateral recumbency on a heating pad, to maintain body temperature. Indwelling PE-50 catheters were placed in the carotid artery for measurements of mean arterial blood pressure and PV-1 catheters were inserted into the pulmonary artery, via the jugular vein, to measure pulmonary arterial pressure as described [10], [20]. Collection of arterial pressure data via a fluid-filled pressure transducer as was described [10]. "
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