Editorial: Hemopexin: newest member of the anti-inflammatory mediator club

Fink, Mitchell P.

doi:10.1189/jlb.0309137

Cited by 14 publications

(15 citation statements)

References 18 publications

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“…This indicates that Hx may confer protection against heme-driven endothelial activation, oxidative stress, and inflammation. 43 The vascular dysfunction common to both β-thalassemia and SCD is further amplified by the reduced bioavailability of NO as major vasodilator, resulting in imbalance of vascular tone toward vasoconstriction. 4,11,22,44,45 In β-thalassemia and SCD, consumption/inactivation of NO is accelerated by the synergistic effects of chronic oxidative stress and persistent hemolysis.…”

Section: Discussionmentioning

confidence: 99%

Hemopexin Therapy Improves Cardiovascular Function by Preventing Heme-Induced Endothelial Toxicity in Mouse Models of Hemolytic Diseases

et al. 2013

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Background-Hemolytic diseases are characterized by enhanced intravascular hemolysis resulting in heme-catalyzed reactive oxygen species generation, which leads to endothelial dysfunction and oxidative damage. Hemopexin (Hx) is a plasma heme scavenger able to prevent endothelial damage and tissue congestion in a model of heme overload. Here, we tested whether Hx could be used as a therapeutic tool to counteract heme toxic effects on the cardiovascular system in hemolytic diseases. Methods and Results-By using a model of heme overload in Hx-null mice, we demonstrated that heme excess in plasma, if not bound to Hx, promoted the production of reactive oxygen species and the induction of adhesion molecules and caused the reduction of nitric oxide availability. Then, we used β-thalassemia and sickle cell disease mice as models of hemolytic diseases to evaluate the efficacy of an Hx-based therapy in the treatment of vascular dysfunction related to heme overload. Our data demonstrated that Hx prevented heme-iron loading in the cardiovascular system, thus limiting the production of reactive oxygen species, the induction of adhesion molecules, and the oxidative inactivation of nitric oxide synthase/nitric oxide, and promoted heme recovery and detoxification by the liver mainly through the induction of heme oxygenase activity. Moreover, we showed that in sickle cell disease mice, endothelial activation and oxidation were associated with increased blood pressure and altered cardiac function, and the administration of exogenous Hx was found to almost completely normalize these parameters. 12,13,16 In hemolytic diseases, the high rate of hemolysis results in the saturation and depletion of the plasma Hb/heme scavenging systems 17 and leads to a buildup of Hb and heme in the circulation that mediates pro-oxidant and proinflammatory effects on vessel endothelial cells. Conclusions-Hemopexin 18Although many mechanisms contribute to the complex pathophysiology of hemolytic diseases as SCD and β-thalassemia, a unifying theme is represented by the dysfunction of the vascular endothelium and the highly pro-oxidant plasma environment. 1,[19][20][21][22] SCD is characterized by recurring episodes of painful vasoocclusion, leading to ischemia/reperfusion injury and organ damage.6,23 Endothelial dysfunction, inflammation, and activated monocytes, neutrophils, platelets, and dense red cells all contribute to sickle cell crisis.4,23 β -Thalassemia is frequently complicated by thromboembolic events resulting from coagulation abnormalities and damaged red cells exposing phosphatidylserine, to which endothelial activation and oxidative stress strongly contribute. 3,23,24 Moreover, severe forms of SCD and β-thalassemia require a blood transfusion regimen that further increases the amount of circulating Hb/heme, thus exacerbating oxidative stress. 25,26 Although an iron chelation therapy is routinely associated with a transfusion regimen, 27,28 no heme chelation therapy has been developed to date that specifically prevents heme-induced endot...

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Section: Discussionmentioning

confidence: 99%

Hemopexin Therapy Improves Cardiovascular Function by Preventing Heme-Induced Endothelial Toxicity in Mouse Models of Hemolytic Diseases

et al. 2013

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“…Haptoglobin and haemopexin are acute-phase proteins typically secreted by the liver as a stress response (Guillouzo et al 1984) though they are also secreted by other organs in response to acute injury (Zager et al 2012). Both will act to reduce oxidative stress through antioxidant action or through haem binding (Tseng et al 2004, Tolosano et al 2010, while haemopexin also has potent anti-inflammatory effects (Fink 2009). Lactoperoxidase, in contrast, is a natural antibacterial agent usually associated with exocrine glands (Pruitt & Reiter 1985).…”

Section: Discussionmentioning

confidence: 99%

Identification of Leydig cell-specific mRNA transcripts in the adult rat testis

O’Shaughnessy¹,

Monteiro²,

Fowler³

et al. 2014

Reproduction

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The adult population of Leydig cells acts to secrete testosterone which is essential for reproductive health and fertility in the adult male. However, other physiological functions of these cells are uncertain, and to address this issue a cell ablation model has been used to identify Leydig cell-specific mRNA transcripts. Ethane dimethane sulphonate (EDS) was synthesised by a novel process and was used to ablate Leydig cells in adult male rats previously treated with butane dimethane sulphonate (busulphan) to delete the germ cell population. Levels of mRNA transcripts were measured in the testis using microarrays 1, 3, 5, 8 and 12 days after EDS injection. During this period, there was a significant change in the levels of 2200 different transcripts with a marked decline in the levels of canonical Leydig cell transcripts, such as Cyp11a1, Cyp17a1 and Insl3. A total of 95 transcripts showed a similar decline in expression after EDS treatment, suggesting that they have a Leydig cell-specific origin. Analysis of selected transcripts confirmed that they were expressed specifically in Leydig cells and showed that most had a late onset of expression during adult Leydig cell development. Apart from transcripts encoding components of the steroidogenic apparatus, the most common predicted function of translated proteins was endogenous and xenotoxicant metabolism. In addition, a number of transcripts encode acute-phase proteins involved in reduction of oxidative stress. Results show that, in addition to androgen secretion, Leydig cells may have a critical role to play in protecting the testis from damage caused by toxicants or stress.

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“…This could occur either by 1) free heme binding, 2) heme-Hpx induction of cytoprotective HO-1 (22), or 3) by exerting a direct antioxidant effect, e.g., as noted above. Despite this multiplicity of actions, as well as its ability to impact tissue inflammation (7,12,13,23), the ultimate impact of renal Hpx accumulation on the evolution of AKI remains to be defined. However, based on all of the above, it does seem highly likely that pathophysiologic links between the acute hepatic stress response, Hpx generation, and kidney injury exist.…”

Section: Discussionmentioning

confidence: 99%

“…For example, due to an intrinsic protease activity, Hpx can induce nephrindependent reorganization of the podocyte cytoskeleton, leading to proteinuria (11). In addition, recent evidence suggests that Hpx can exert potent anti-inflammatory effects (7,12,13,23). As just one example, when macrophages are exposed to endotoxin in the presence of Hpx, decreased proinflammatory cytokine generation results (12).…”

mentioning

confidence: 99%

Renal cortical hemopexin accumulation in response to acute kidney injury

Zager

Johnson

Becker

2012

American Journal of Physiology-Renal Physiology

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Hemopexin (Hpx) is a liver-generated acute phase reactant that binds and neutralizes prooxidant free heme. This study tested whether acute kidney injury (AKI) triggers renal Hpx accumulation, potentially impacting heme Fe-mediated tubular injury. Mice were subjected to glycerol, cisplatin, ischemia-reperfusion (I/R), or endotoxemic [lipopolysaccharide (LPS)] AKI. In each instance, 3- to 30-fold renal cortical and isolated proximal tubule segment (PTS) Hpx increases resulted. Although renal cortex and PTS showed variable Hpx mRNA increases, due, in part, to increased mRNA stability, mRNA levels did not correlate with renal Hpx protein accumulation. Conversely, AKI evoked three- to fourfold increases in hepatic Hpx gene induction, which corresponded with three- to fourfold plasma Hpx increases. Renal immunohistochemistry, and increased urinary Hpx excretion, indicated that circulating Hpx gains tubule luminal/urinary access, followed by proximal tubule endocytic uptake. Paradoxically, in cultured renal cells (HK-2, HEK-293), Fe depletion, and not free heme excess, increased Hpx mRNA. LPS acutely increased HK-2 cell Hpx mRNA. This finding, coupled with observations that LPS evoked ∼30-fold greater renal Hpx mRNA increases than any other AKI model, suggests that inflammation, not heme exposure, activates the renal Hpx gene. Each form of AKI evoked early increases in circulating free heme, which subsequently fell to subnormal levels as plasma Hpx rose. In addition, purified Hpx blunted free Fe-mediated HK-2 cell death. In sum, these data indicated that AKI-associated hepatic stress generates Hpx, which gains renal tubule access. Given its ability to bind free heme and mitigate free Fe toxicity, Hpx loading can potentially confer cytoprotective effects.

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Editorial: Hemopexin: newest member of the anti-inflammatory mediator club

Abstract: Abbreviations: HMGB1ϭhigh mobility group box 1, HO-1ϭheme oxygenase 1, KOϭknockout, Pam3Cysϭtripalmitoyl-S-glyceryl cysteine Editorial 0741-5400/09/0086-203

Cited by 14 publications

References 18 publications

Hemopexin Therapy Improves Cardiovascular Function by Preventing Heme-Induced Endothelial Toxicity in Mouse Models of Hemolytic Diseases

Hemopexin Therapy Improves Cardiovascular Function by Preventing Heme-Induced Endothelial Toxicity in Mouse Models of Hemolytic Diseases

Identification of Leydig cell-specific mRNA transcripts in the adult rat testis

Renal cortical hemopexin accumulation in response to acute kidney injury

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