Heme Scavenging by Hemopexin Attenuates Sepsis-Induced Proinflammatory Cytokines and Kidney Insuffciency in a Humanized Mouse Model of Sickle Cell Disease

Abstract

Sickle cell disease (SCD) is a genetic blood disorder characterized by abnormal hemoglobin production, leading to sickle-shaped red blood cells (RBC). Alteration in RBC shape results in vasoocclusion, chronic hemolysis, and multiple organ damage. One of the severe complications of SCD is an increased susceptibility to infections, including sepsis, which can be life-threatening. Kidney injury, a common and severe complication of sepsis, contributes to the complexity and poor outcomes associated with morbidity and mortality in SCD. However, the mechanisms that underlie septic acute kidney injury (AKI) in SCD are poorly understood. Here, we examined the effects of sepsis in transgenic homozygous SCD (SS; Townes model) mice and their non-sickling (AA) counterparts. We tested the hypothesis that aggravation of inflammation and oxidative stress by free heme released during hemolysis contribute to sepsis-induced kidney insuffciency in SCD. AA and SS mice were subjected to 18 h of sham operation and cecal ligation and puncture (CLP), a pre-clinical model of polymicrobial sepsis, after which kidney function was evaluated by transdermal measurement of glomerular filtration rate (GFR). AKI biomarkers, renal oxidative stress, and cytokines levels were also investigated. We demonstrate that mid- to high-grade CLP (ligation of 60-75% of the cecum and multiple punctures with 21-gauge needles) caused 100% mortality in SS mice. Unlike AA mice (100% survival), SS mice subjected to low-grade CLP (LgCLP; ligation of <45% of the cecum and a single puncture with 21-gauge needles) exhibited 40% survival. LgCLP reduced body weight but did not exacerbate splenomegaly in SS mice. Basal plasma bilirubin, heme, and ferritin were significantly higher in SS than in AA mice. In contrast to AA, LgCLP amplified the increase in plasma bilirubin, heme, and ferritin in SS mice. LgCLP also decreased GFR and increased renal oxidative stress, AKI biomarkers, and kidney-to-body weight ratio in SS mice. Luminex multiplex cytokine analysis indicated that the plasma levels of multiple pro-inflammatory cytokines were elevated in septic SS mice. Heme scavenger hemopexin (HX) diminished LgCLP-induced plasma heme increase. HX also mitigated kidney insuffciency, inflammation, and mortality in the septic SS mice. Our findings suggest that free heme contributes to septic AKI in SCD mice and that HX therapy may attenuate the harmful effect of heme in SCD during sepsis. NHLBI: R01 HL151735. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.