Can haptoglobin attenuate hemoglobin‐induced vascular damage?

Abstract

Hemolytic diseases and infections can lead to intravascular hemolysis, which causes increased plasma hemoglobin (Hb) concentration. Over time, this “cell free Hb” is toxic to the blood vessels, exerting oxidative damage, nitric oxide (NO) scavenging, or inflammatory responses within the vasculature. The exposure of increased Hb on the lung tissue can lead to pulmonary hypertension (PH), which is high blood pressure in the pulmonary arteries due to changes in arterial wall. Haptaglobin is an acute phase protein responsible for binding and clearance of Hb. We hypothesized that haptoglobin (Hp) can attenuate PH secondarily to vascular hemoglobin exposure. To test our hypothesis, Hb was chronically administered to rats at physiologically relevant concentrations as observed in the sickle cell disease (SCD) (0.2 μmole/day) for 5 weeks. To further mimic the SCD process, rats were placed in hypobaric hypoxic chambers (~17,000 ft). Animals were divided into 4 groups; (1) Control (sham), (2) Hb infusion, (3) Hp injections (biweekly), and (4) Hb: Hp (chronically infused with Hb treated biweekly with Hp). At the end of the 5 weeks, we evaluated pulmonary blood pressure, cardiac output, and pulmonary vascular wall thickness. Additionally, lung analysis for indicators of endothelial nitric oxide synthase (eNOS) and intercellular adhesion molecule 1 (ICAM‐1) expression were performed. Preliminary data demonstrates that groups infused with haptoglobin had lower pulmonary blood pressure, decreased vessel wall thickness, and decreased ICAM‐1 expression. We observed no difference in eNOS expression between groups. This suggests that Hb induced inflammation may be attenuated by Hp.