Free hemoglobin induction of pulmonary vascular disease: evidence for an inflammatory mechanism.
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.
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.
Paul W
PW
Buehler
Jin Hyen
JH
Baek
Christina
C
Lisk
Ian
I
Connor
Tim
T
Sullivan
Douglas
D
Kominsky
Susan
S
Majka
Kurt R
KR
Stenmark
Eva
E
Nozik-Grayck
Joe
J
Bonaventura
David C
DC
Irwin
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D002302:Cardiac Output / Q000187:drug effects; D003497:Cyclic N-Oxides / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects; D006454:Hemoglobins / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007249:Inflammation / Q000150:complications / Q000473:pathology*; D007260:Infusion Pumps; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D015227:Lipid Peroxidation / Q000187:drug effects; D008168:Lung / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008171:Lung Diseases / Q000097:blood / Q000139:chemically induced* / Q000473:pathology / Q000652:urine; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011651:Pulmonary Artery / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013113:Spin Labels; D014652:Vascular Diseases / Q000097:blood / Q000139:chemically induced* / Q000473:pathology / Q000652:urine
D003497:Cyclic N-Oxides; D006454:Hemoglobins; D013113:Spin Labels; D018799:Intercellular Adhesion Molecule-1; D009569:Nitric Oxide; D006861:Hydrogen Peroxide; C001803:tempol