Inhibition of Neutrophil Migration by Hemopexin Leads to Increased Mortality Due to Sepsis in Mice

Abstract

These data demonstrate for the first time the inhibitory role of hemopexin in neutrophil migration during sepsis and suggest that the therapeutic inhibition of hemopexin or its protease activity could improve neutrophil migration to the focus of infection and survival in sepsis.

Hemolysis and free hemoglobin revisited: exploring hemoglobin and hemin scavengers as a novel class of therapeutic proteins

“…The outcome of such activities has been noted as anti-inflammatory in some cases (eg, Hpx attenuates inflammatory cytokine secretion by lipopolysaccharide-stimulated macrophages 83 ), whereas impaired bacterial clearance was found as a consequence of suppressed neutrophil migration in other mouse studies. 84 At this point, it is unknown whether such non-heminrelated effects of Hpx are an inherent activity of the protein itself or if they are side effects caused by impurities or degradation products in some preparations of plasma-derived Hpx. 85 In mouse models of malaria, Hb/hemin-driven oxidative damage and NO depletion were linked to the evolution of cerebral malaria.…”

Purified and Recombinant Hemopexin: Protease Activity and Effect on Neutrophil Chemotaxis

“…injection of thioglycollate and was measured in mice with administration of Hx as described by Spiller et al (25). The Institutional Animal Care and Use Committee at Massachusetts General Hospital approved the animal protocols used in this study.…”

“…Amidolytic Assays on Hxs were performed as described previously with modifications (25). Two serine protease chromogenic substrates were used to as well as endogenous mediators such as high-mobility group box protein 1 (HMGB1) to induce proinflammatory cytokines TNF and interleukin-6 (IL-6) from macrophages (12)(13)(14).…”

“…However, questions have been raised as to the safety of Hx infusion because of possible protease activity of Hx (22)(23)(24) and possible effects of Hx on neutrophil chemotaxis in a different study (25).…”

Cell-Free Hemoglobin and Its Scavenger Proteins: New Disease Models Leading the Way to Targeted Therapies

“…Nonhemebinding effects of Hpx might be responsible for the intriguing observation that, in another mouse model of sepsis, Hpx inhibited neutrophil migration to the focus of infection. In this model, lethality was paradoxically increased in septic wild-type mice treated with the hemebinding protein, and reduced in Hpx-knockout animals (Spiller et al 2011). It was suggested that many of the reported nonheme-binding functions of Hpx were related to the experimental conditions or to impurities and degradation products in some experimental Hpx preparations (Mauk et al 2011); careful examination of such effects may be critical in the preclinical evaluation of Hpx-based therapeutics.…”