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HO-1 prevents heme-driven severe sepsis. ( A ) Hemoglobin and haptoglobin plasma concentrations in Hmox1 +/+ ( n = 10), Hmox1 +/ − ( n =
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Low-grade polymicrobial infection induced by cecal ligation and puncture is lethal in heme oxygenase-1-deficient mice (Hmox1(-/-)), but not in wild-type (Hmox1(+/+)) mice. Here we demonstrate that the protective effect of this heme-catabolizing enzyme relies on its ability to prevent tissue damage caused by the circulating free heme released from h...
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... of several cytokines involved in the pathogenesis of se- vere sepsis [for example, TNF, interleukin-6 (IL-6), and IL-10] was similar in Hmox1 −/− versus Hmox1 +/− or Hmox1 +/+ mice subjected to low-grade CLP ( fig. S2, A, D, and G). Likewise, peritoneal or bone marrow- derived monocytes/macrophages (Mø) from Hmox1 −/− versus Hmox1 +/+ mice produced similar amounts of IL-6 when exposed in vitro to bac- terial lipopolysaccharide (LPS) or to live bacteria (fig. S2, E and F), while producing slightly but significantly higher amounts of TNF when exposed to LPS ...
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... or bone marrow- derived monocytes/macrophages (Mø) from Hmox1 −/− versus Hmox1 +/+ mice produced similar amounts of IL-6 when exposed in vitro to bac- terial lipopolysaccharide (LPS) or to live bacteria (fig. S2, E and F), while producing slightly but significantly higher amounts of TNF when exposed to LPS (fig. S2B) but not to live bacteria ( fig. S2C). Higher production of IL-10 also occurred in Hmox1 −/− versus Hmox1 +/+ Mø exposed to LPS or to live bacteria ( fig. S2, H and I). Because HO-1 reg- ulates the expression of a subset of cytokines, including IL-10 (fig. S2, H and I) in response to bacterial agonists such as LPS ( fig. S2H) or live bacteria ( fig. S2I), we cannot ...
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... when exposed in vitro to bac- terial lipopolysaccharide (LPS) or to live bacteria (fig. S2, E and F), while producing slightly but significantly higher amounts of TNF when exposed to LPS (fig. S2B) but not to live bacteria ( fig. S2C). Higher production of IL-10 also occurred in Hmox1 −/− versus Hmox1 +/+ Mø exposed to LPS or to live bacteria ( fig. S2, H and I). Because HO-1 reg- ulates the expression of a subset of cytokines, including IL-10 (fig. S2, H and I) in response to bacterial agonists such as LPS ( fig. S2H) or live bacteria ( fig. S2I), we cannot exclude that this effect might contribute to the protective mechanism by which HO-1 suppresses the patho- genesis of severe ...
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... when exposed to LPS (fig. S2B) but not to live bacteria ( fig. S2C). Higher production of IL-10 also occurred in Hmox1 −/− versus Hmox1 +/+ Mø exposed to LPS or to live bacteria ( fig. S2, H and I). Because HO-1 reg- ulates the expression of a subset of cytokines, including IL-10 (fig. S2, H and I) in response to bacterial agonists such as LPS ( fig. S2H) or live bacteria ( fig. S2I), we cannot exclude that this effect might contribute to the protective mechanism by which HO-1 suppresses the patho- genesis of severe ...
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... but not to live bacteria ( fig. S2C). Higher production of IL-10 also occurred in Hmox1 −/− versus Hmox1 +/+ Mø exposed to LPS or to live bacteria ( fig. S2, H and I). Because HO-1 reg- ulates the expression of a subset of cytokines, including IL-10 (fig. S2, H and I) in response to bacterial agonists such as LPS ( fig. S2H) or live bacteria ( fig. S2I), we cannot exclude that this effect might contribute to the protective mechanism by which HO-1 suppresses the patho- genesis of severe ...
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... stress (11). We asked whether increased mortality of Hmox1 −/− mice subjected to polymicrobial infection was associated with increased hemolysis, as well as with the accumulation of cell-free hemoglobin and/or free heme in plasma (11). When subjected to low-grade CLP, Hmox1 −/− mice, but not Hmox1 +/+ mice, accumulated extracellular hemoglobin ( Fig. 2A) and free heme in plasma (Fig. 2B), whereas plasma concentra- tions of the hemoglobin-binding protein haptoglobin (15) (Fig. 2A) and the heme-binding protein hemopexin (HPX) (16) were decreased (Fig. 2B). Fig. 1. HO-1 affords tolerance against polymicrobial infection in mice. (A) Hmox1 messenger RNA (mRNA) expression in peritoneal ...
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... mortality of Hmox1 −/− mice subjected to polymicrobial infection was associated with increased hemolysis, as well as with the accumulation of cell-free hemoglobin and/or free heme in plasma (11). When subjected to low-grade CLP, Hmox1 −/− mice, but not Hmox1 +/+ mice, accumulated extracellular hemoglobin ( Fig. 2A) and free heme in plasma (Fig. 2B), whereas plasma concentra- tions of the hemoglobin-binding protein haptoglobin (15) (Fig. 2A) and the heme-binding protein hemopexin (HPX) (16) were decreased (Fig. 2B). Fig. 1. HO-1 affords tolerance against polymicrobial infection in mice. (A) Hmox1 messenger RNA (mRNA) expression in peritoneal leukocytes (Perit. leu.), lung, liver, ...
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... hemolysis, as well as with the accumulation of cell-free hemoglobin and/or free heme in plasma (11). When subjected to low-grade CLP, Hmox1 −/− mice, but not Hmox1 +/+ mice, accumulated extracellular hemoglobin ( Fig. 2A) and free heme in plasma (Fig. 2B), whereas plasma concentra- tions of the hemoglobin-binding protein haptoglobin (15) (Fig. 2A) and the heme-binding protein hemopexin (HPX) (16) were decreased (Fig. 2B). Fig. 1. HO-1 affords tolerance against polymicrobial infection in mice. (A) Hmox1 messenger RNA (mRNA) expression in peritoneal leukocytes (Perit. leu.), lung, liver, and kidney after low-grade CLP in BALB/c mice, as deter- mined by quantitative RT-PCR. Data ...
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... and/or free heme in plasma (11). When subjected to low-grade CLP, Hmox1 −/− mice, but not Hmox1 +/+ mice, accumulated extracellular hemoglobin ( Fig. 2A) and free heme in plasma (Fig. 2B), whereas plasma concentra- tions of the hemoglobin-binding protein haptoglobin (15) (Fig. 2A) and the heme-binding protein hemopexin (HPX) (16) were decreased (Fig. 2B). Fig. 1. HO-1 affords tolerance against polymicrobial infection in mice. (A) Hmox1 messenger RNA (mRNA) expression in peritoneal leukocytes (Perit. leu.), lung, liver, and kidney after low-grade CLP in BALB/c mice, as deter- mined by quantitative RT-PCR. Data are shown as mean ± SD (n = 3 per group). (B) Survival of Hmox1 +/+ (n = 15), ...
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... then asked whether accumulation of free heme in plasma contributes to the pathogenesis of severe sepsis. Heme administration to wild-type (Hmox1 +/+ ) mice subjected to low-grade CLP led to se- vere sepsis (77% mortality) (Fig. 2C), characterized by multiple end- stage organ failure, as revealed serologically by increased AST, BUN, and CPK plasma concentrations (Fig. 2D). Organ damage was con- firmed histologically (Fig. 2E). Heme administration to naïve wild-type (Hmox1 +/+ ) mice, although not lethal per se (0% mortality), elicited kidney, but not liver or ...
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... accumulation of free heme in plasma contributes to the pathogenesis of severe sepsis. Heme administration to wild-type (Hmox1 +/+ ) mice subjected to low-grade CLP led to se- vere sepsis (77% mortality) (Fig. 2C), characterized by multiple end- stage organ failure, as revealed serologically by increased AST, BUN, and CPK plasma concentrations (Fig. 2D). Organ damage was con- firmed histologically (Fig. 2E). Heme administration to naïve wild-type (Hmox1 +/+ ) mice, although not lethal per se (0% mortality), elicited kidney, but not liver or cardiac, damage (Fig. 2D). Heme administra- LG CLP (n = 6), or HG CLP (n = 11 to 12). Circles represent individual mice. Bars represent median ...
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... the pathogenesis of severe sepsis. Heme administration to wild-type (Hmox1 +/+ ) mice subjected to low-grade CLP led to se- vere sepsis (77% mortality) (Fig. 2C), characterized by multiple end- stage organ failure, as revealed serologically by increased AST, BUN, and CPK plasma concentrations (Fig. 2D). Organ damage was con- firmed histologically (Fig. 2E). Heme administration to naïve wild-type (Hmox1 +/+ ) mice, although not lethal per se (0% mortality), elicited kidney, but not liver or cardiac, damage (Fig. 2D). Heme administra- LG CLP (n = 6), or HG CLP (n = 11 to 12). Circles represent individual mice. Bars represent median values. (F) Survival of wild-type (Hmox1 +/+ ) BALB/c mice ...
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... characterized by multiple end- stage organ failure, as revealed serologically by increased AST, BUN, and CPK plasma concentrations (Fig. 2D). Organ damage was con- firmed histologically (Fig. 2E). Heme administration to naïve wild-type (Hmox1 +/+ ) mice, although not lethal per se (0% mortality), elicited kidney, but not liver or cardiac, damage (Fig. 2D). Heme administra- LG CLP (n = 6), or HG CLP (n = 11 to 12). Circles represent individual mice. Bars represent median values. (F) Survival of wild-type (Hmox1 +/+ ) BALB/c mice subjected to high-grade CLP. Mice received purified rabbit HPX (50 mg/kg ip; n = 9), purified rabbit polyclonal IgG (50 mg/kg ip; n = 16), or vehicle ...
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... 24 to 36 hours after CLP (time of death). *P < 0.05; **P < 0.01; ***P < 0.001; ns, not significant. tion was also not lethal in mice subjected to sham laparotomy (0% mor- tality). Moreover, "iron-free" protoporphyrin IX failed to cause organ damage or to precipitate severe sepsis when administered to mice subjected to low-grade CLP (0% mortality) (Fig. 2C). These observa- tions demonstrate that free heme can precipitate the onset of severe sepsis in mice subjected to an otherwise benign (nonlethal) poly- microbial infection. They also reveal that the kidney is particularly vul- nerable to the damaging effects of free ...
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... number of CFUs in the peritoneum and blood was similar in mice subjected to low-grade CLP whether or not they received heme thereafter (Fig. 2F). This demonstrated that the ability of free heme to precipitate severe sepsis in mice (Fig. 2C) was not associated with increased pathogen load (Fig. 2F), thus revealing that free heme com- promised host tolerance against polymicrobial infection. This notion was strongly supported by the observation that administration of free heme to ...
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... number of CFUs in the peritoneum and blood was similar in mice subjected to low-grade CLP whether or not they received heme thereafter (Fig. 2F). This demonstrated that the ability of free heme to precipitate severe sepsis in mice (Fig. 2C) was not associated with increased pathogen load (Fig. 2F), thus revealing that free heme com- promised host tolerance against polymicrobial infection. This notion was strongly supported by the observation that administration of free heme to wild-type (Hmox1 +/+ ) mice subjected to a sublethal dose of heat-killed bacteria led to 100% ...
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... number of CFUs in the peritoneum and blood was similar in mice subjected to low-grade CLP whether or not they received heme thereafter (Fig. 2F). This demonstrated that the ability of free heme to precipitate severe sepsis in mice (Fig. 2C) was not associated with increased pathogen load (Fig. 2F), thus revealing that free heme com- promised host tolerance against polymicrobial infection. This notion was strongly supported by the observation that administration of free heme to wild-type (Hmox1 +/+ ) mice subjected to a sublethal dose of heat-killed bacteria led to 100% mortality, as compared to 12.5% mor- tality in control mice ...
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... revealing that free heme com- promised host tolerance against polymicrobial infection. This notion was strongly supported by the observation that administration of free heme to wild-type (Hmox1 +/+ ) mice subjected to a sublethal dose of heat-killed bacteria led to 100% mortality, as compared to 12.5% mor- tality in control mice receiving vehicle (Fig. ...
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... pathogens can cause hemolysis (25) and hence lead to accumulation of extracellular hemoglobin in the circulation. Oxidation of cell-free hemoglobin can be highly deleterious to the host in at least three ways. First, it can exacerbate inflammation (26). Second, it can release heme (Figs. 2, A and B, and 3D) (14), a putative source of iron that can promote microbial growth (27). Third, as shown herein, free heme can be highly cytotoxic in the presence of proinflammatory ago- nists (Fig. 4B) (11), causing irreversible tissue damage and organ fail- ure (Fig. 2, D and E), the hallmarks of severe sepsis (2) (Fig. ...
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... First, it can exacerbate inflammation (26). Second, it can release heme (Figs. 2, A and B, and 3D) (14), a putative source of iron that can promote microbial growth (27). Third, as shown herein, free heme can be highly cytotoxic in the presence of proinflammatory ago- nists (Fig. 4B) (11), causing irreversible tissue damage and organ fail- ure (Fig. 2, D and E), the hallmarks of severe sepsis (2) (Fig. ...
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... heme-driven tissue damage can contribute to the patho- genesis of severe sepsis is suggested by four independent lines of ev- idence. First, exacerbated mortality of Hmox1 −/− mice subjected to microbial infection (Fig. 1B) correlated with the accumulation of free heme in the plasma (Fig. 2B). Second, administration of free heme to wild-type (Hmox1 +/+ ) mice subjected to low-grade (nonlethal) microbi- al infection was sufficient to elicit a lethal form of severe sepsis (Fig. 2C). Third, free heme accumulated in the plasma of wild-type (Hmox1 +/+ ) mice subjected to high-grade (lethal), but not low-grade, microbial in- ...
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... idence. First, exacerbated mortality of Hmox1 −/− mice subjected to microbial infection (Fig. 1B) correlated with the accumulation of free heme in the plasma (Fig. 2B). Second, administration of free heme to wild-type (Hmox1 +/+ ) mice subjected to low-grade (nonlethal) microbi- al infection was sufficient to elicit a lethal form of severe sepsis (Fig. 2C). Third, free heme accumulated in the plasma of wild-type (Hmox1 +/+ ) mice subjected to high-grade (lethal), but not low-grade, microbial in- fection (Fig. 3, A and D). Fourth, sequestration of free heme by HPX suppressed the development of severe sepsis in wild-type (Hmox1 +/+ ) mice subjected to high-grade microbial infection (Fig. ...
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Background
Trauma is the leading cause of death and disability in patients aged 1–46 y. Severely injured patients experience considerable blood loss and hemorrhagic shock requiring treatment with massive transfusion of red blood cells (RBCs). Preclinical and retrospective human studies in trauma patients have suggested that poorer therapeutic effic...
Citations
... Whether this reflects a normal situation in children or reflects underlying disease is not clear. Either way, this level of CFH has been shown to elicit cell permeability and injury [10,11,18]. Notably, hemopexin levels were higher in all patients immediately post-CPB to the extent that the ratio with CFH was above one, a condition expected to prevent CFH toxicity. ...
... This understanding stems largely from hemolytic disease (e.g., sickle cell disease) and experiences with CFH-based blood substitutes [19][20][21]. More recent evidence suggests that hemolysis plays a role in non-hemolytic acuate inflammatory diseases, especially in critical care settings (e.g., sepsis, infection, stored RBC transfusion, and associated end-organ injury), leading to a renewed focus on understanding various species that are released during hemolysis and the mechanisms linking these to increased inflammation and oxidative tissue injury [18,[22][23][24][25][26][27][28]. It is now clear that in addition to CFH, free heme and iron are all independent mediators of toxic effects associated with hemolysis. ...
Background/Objectives: Hemolysis has been associated with acute kidney injury (AKI) in infants and neonates after surgery involving cardiopulmonary bypass (CPB). Erythrocyte hemolysis and subsequent end-organ injury have been shown to be a complex process involving the liberation of multiple molecules that mediate the loss of nitric oxide and oxidative damage. This study assesses the association of multiple products of erythrocyte hemolysis with the evolution of AKI in neonates and infants undergoing CPB surgery. Methods: Blood and urine samples were collected at multiple time points before and after CPB and stored within an institutional biorepository. Twenty-one patients with AKI were matched with twenty-one non-Aki patients based on demographic and case complexity data. Results: Samples were analyzed for cell-free hemoglobin, heme, non-transferrin-bound iron, haptoglobin, hemopexin, and nitrite/nitrate. NGAL and KIM-1 were measured to index AKI. Cell-free hemoglobin was higher, haptoglobin was lower, and haptoglobin:hemoglobin ratio was lower in AKI compared to non-AKI patients. Conclusions: AKI in neonates and infants after CPB is associated with a pre and postoperative decrease in serum haptoglobin. These results confirm the need for future studies to prevent injury from hemolysis during CPB and potentially identify at-risk patients with decreased haptoglobin levels before surgery if delay is an option.
... Since severe cases of HUS frequently require dialysis and pose the risk of progression to chronic and end-stage kidney disease [4,7], it is important to further elucidate the underlying mechanisms involved in HUS pathogenesis and to identify molecular targets for new potential therapeutic approaches. There is evidence that free heme propagates disease progression in hemolytic disorders and life-threatening infections [8][9][10], including sepsis [8], malaria [10] and sickle cell disease [11][12][13][14]. The degradation of heme into equimolar amounts of ferrous iron, carbon monoxide (CO) and biliverdin is catalyzed by heme oxygenases (HO) which are intracellular enzymes found in humans and mice [15]. ...
... Since severe cases of HUS frequently require dialysis and pose the risk of progression to chronic and end-stage kidney disease [4,7], it is important to further elucidate the underlying mechanisms involved in HUS pathogenesis and to identify molecular targets for new potential therapeutic approaches. There is evidence that free heme propagates disease progression in hemolytic disorders and life-threatening infections [8][9][10], including sepsis [8], malaria [10] and sickle cell disease [11][12][13][14]. The degradation of heme into equimolar amounts of ferrous iron, carbon monoxide (CO) and biliverdin is catalyzed by heme oxygenases (HO) which are intracellular enzymes found in humans and mice [15]. ...
... While the ubiquitously expressed HO-1 isoform is induced during inflammatory or oxidative conditions, HO-2 is constitutively expressed in various tissues [16]. Nevertheless, it has been demonstrated that HO-2 is less effective in exerting a cytoprotective function against substantial quantities of free heme during hemolysis [17,18], whereas HO-1 allows the efficient recycling of heme-bound iron under hemolytic conditions which would otherwise cause oxidative stress [19] and inflammation [8,20]. The induction of HO-1, encoded by the gene heme oxygenase-1 (Hmox1), is associated with various anti-inflammatory, anti-proliferative as well as anti-apoptotic responses in answer to diverse stress conditions [16,17]. ...
Hemolytic-uremic syndrome (HUS) is a systemic complication of an infection with Shiga toxin (Stx)-producing enterohemorrhagic Escherichia coli, primarily leading to acute kidney injury (AKI) and microangiopathic hemolytic anemia. Although free heme has been found to aggravate renal damage in hemolytic diseases, the relevance of the heme-degrading enzyme heme oxygenase-1 (HO-1, encoded by Hmox1) in HUS has not yet been investigated. We hypothesized that HO-1, also important in acute phase responses in damage and inflammation, contributes to renal pathogenesis in HUS. The effect of tamoxifen-induced Hmox1 gene deletion on renal HO-1 expression, disease progression and AKI was investigated in mice 7 days after HUS induction. Renal HO-1 levels were increased in Stx-challenged mice with tamoxifen-induced Hmox1 gene deletion (Hmox1R26Δ/Δ) and control mice (Hmox1lox/lox). This HO-1 induction was significantly lower (−43%) in Hmox1R26Δ/Δ mice compared to Hmox1lox/lox mice with HUS. Notably, the reduced renal HO-1 expression was associated with an exacerbation of kidney injury in mice with HUS as indicated by a 1.7-fold increase (p = 0.02) in plasma neutrophil gelatinase-associated lipocalin (NGAL) and a 1.3-fold increase (p = 0.06) in plasma urea, while other surrogate parameters for AKI (e.g., periodic acid Schiff staining, kidney injury molecule-1, fibrin deposition) and general disease progression (HUS score, weight loss) remained unchanged. These results indicate a potentially protective role of HO-1 in the pathogenesis of Stx-mediated AKI in HUS.
... During sepsis-induced anemia, cell-free hemoglobin (CFH) is released by erythrocytes through a series of mechanisms [4]. Traditionally, free heme and CFH-damaged tissue have been observed to worsen sepsis in lipopolysaccharide-induced systemic inflammatory animal models [5,6]. Clinical studies have shown that higher levels of CFH in patients with sepsis are associated with lower survival rates [7,8]. ...
Background: Sepsis is a leading cause of mortality in intensive care units (ICUs). Cell-free hemoglobin (CFH) released during sepsis interacts with lysosomal enzymes from neutrophils and macrophages. This study aims to examine the association of LVV-hemorphin-7 (LVV-H7), cathepsin D, and cathepsin G with sepsis and shock in ICU patients. Methods: A prospective observational cohort study was conducted in the medical ICU of a tertiary referral hospital in Taiwan. The patients with an acute increasing sequential organ failure assessment (SOFA) score ≥ 2 between 2022 and 2023. Blood samples from 40 healthy controls were obtained from the hospital biobank. CFH metabolites, including LVV-H7 and lysosomal enzyme cathepsin D and cathepsin G, were compared between the sepsis (definite and probable) and non-sepsis (possible sepsis) groups. Multivariate logistic regression analyzed factors associated with sepsis and shock. Results: Among 120 patients, 75 were classified as septic and 45 as non-septic. Significant differences were observed in CFH, cathepsin D, cathepsin G, and LVV-H7 levels between sepsis and non-sepsis groups. LVV-H7 was a significant predictor for sepsis (adjusted OR [aOR] 1.009, 95% CI 1.005–1.013; p < 0.001) and shock (aOR 1.005, 95% CI 1.002–1.008; p < 0.05). Cathepsin G predicted non-shock (aOR 0.917, 95% CI 0.848–0.991; p < 0.05), while cathepsin D predicted septic shock (aOR 1.001, 95% CI 1.000–1.002; p < 0.05). Conclusions: LVV-H7, cathepsin D, and cathepsin G are associated with the classification of sepsis and shock episodes in critically ill patients with elevated SOFA scores.
... Previous studies have suggested that sepsis patients often have elevated CFH plasma levels, which are independently associated with a higher risk of death [6,19]. Animal studies have also supported these findings [20]. Shaver et al. evaluated the effect of CFH on renal function in an experimental sepsis model, suggesting that CFH exacerbates AKI [21]. ...
Background
Sepsis-associated acute kidney injury (SA-AKI) is common and associated with poor outcomes in critically ill patients. Acetaminophen is often used as an antipyretic and analgesic drug, but the association of acetaminophen use with mortality and recovery of renal function in SA-AKI patients remain unclear. We aimed to investigate the association between acetaminophen use and outcomes in SA-AKI patients.
Methods
This is a retrospective cohort study based on the MIMIC-IV database. Adult patients with SA-AKI were included in the analysis. The exposure was acetaminophen use within 7 days after the onset of SA-AKI. The primary outcome was 28-day mortality. Secondary outcomes included ICU mortality, in-hospital mortality, 90-day mortality, 1-year mortality, and renal recovery. Cox proportional hazards regression models were used to estimate the hazard ratio (HR) with 95% confidence interval (CI) for mortality. Logistic regression models were used to estimate the odd ratio (OR) with 95% CI for renal recovery.
Results
6752 patients with SA-AKI were included, and 3892 (57.6%) patients received acetaminophen. Acetaminophen use was associated with decreased 28-day mortality (HR 0.69, 95% CI 0.63–0.75), ICU mortality (HR 0.56, 95% CI 0.50–0.63), in-hospital mortality (HR 0.62, 95% CI 0.57–0.69), 90-day mortality (HR 0.73, 95% CI 0.68–0.79), and 1-year mortality (HR 0.62, 95% CI 0.57–0.69). Acetaminophen use also was associated with improved renal recovery (OR 1.15, 95% CI 1.04–1.28).
Conclusions
Acetaminophen use is associated with decreased mortality and improved renal recovery in SA-AKI patients.
... [66][67][68] Increased circulating free heme levels have been linked to a higher risk of hemolytic disorders, such as sickle cell anemia, and regulated EC death in patients with severe sepsis. 66,69 Moreover, the excessive release of free heme under pathological conditions is associated with EC barrier dysfunction. In macrophages, heme or the oxidized form of hemoglobin stimulates NLRP3, resulting in the production of the inflammatory factor IL-1β. 70,71 In ECs, heme, rather than hemoglobin, activates the NLRP3 inflammasome, resulting in the release of IL-1β ( Figure 2). ...
... 79 Heme, an important iron-containing compound in the human body, can induce the release of HMGB1 and produce a synergistic effect with it, both participating in the pathogenic mechanism of sepsis. 69 Notably, HMGB1 can affect enzymes involved in heme metabolism, such as HO-1, promoting ferroptosis in ECs. 80 These DAMPs, as part of the DAMP family, influence each other through various pathways and play a pro-inflammatory synergistic role in sepsis. ...
Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Endothelial cells (ECs) are an important cell type typically affected in sepsis, resulting in compromised barrier function and various forms of regulated cell death (RCD). However, the precise mechanisms underlying sepsis-induced EC damage remain unclear. This review summarizes the recent research progress on factors and mechanisms that may affect the permeability and RCD of ECs under septic conditions, including glycocalyx, damage-associated molecular patterns, and various forms of RCD in ECs, such as apoptosis, pyroptosis, ferroptosis, and autophagy. This review offers important insights into the underlying mechanisms of endothelial dysfunction in sepsis, aiming to contribute to developing small-molecule targeted clinical therapies.
... We further demonstrate that IL6 and DEX-mediated induction of the APR is partially protective in CLP. This was somewhat expected because several acute phase proteins (APPs) have protective activities in sepsis and sepsis-like models (Libert et al, 1994a;Hochepied et al, 2000;Van Molle et al, 1997;Dalli et al, 2014;Libert et al, 1996;Janz et al, 2013;Larsen et al, 2010). IL6, via STAT3 activation, also affects the degradation and synthesis of fatty acids in the liver, depending on the context (Gavito et al, 2016). ...
... Besides their recognized anti-inflammatory and/or antimicrobial functions, APPs serve diverse physiological roles. Notably, haptoglobin and hemopexin are pivotal in the clearance of hemoglobin and heme released during hemolysis (Smith and McCulloh, 2015;Larsen et al, 2010), while IL6 and APR stimulate hepatocellular regeneration (Moshage, 1997;Streetz et al, 2000;Cressman et al, 1996;Greenbaum et al, 1998). To conclude, our data suggest that HNF4α dysfunction in sepsis prevents an adequate APR towards IL6, potentially compromising liver regeneration and the removal of hemoglobin and heme during hemolysis. ...
In sepsis, limited food intake and increased energy expenditure induce a starvation response, which is compromised by a quick decline in the expression of hepatic PPARα, a transcription factor essential in intracellular catabolism of free fatty acids. The mechanism upstream of this PPARα downregulation is unknown. We found that sepsis causes a progressive hepatic loss-of-function of HNF4α, which has a strong impact on the expression of several important nuclear receptors, including PPARα. HNF4α depletion in hepatocytes dramatically increases sepsis lethality, steatosis, and organ damage and prevents an adequate response to IL6, which is critical for liver regeneration and survival. An HNF4α agonist protects against sepsis at all levels, irrespectively of bacterial loads, suggesting HNF4α is crucial in tolerance to sepsis. In conclusion, hepatic HNF4α activity is decreased during sepsis, causing PPARα downregulation, metabolic problems, and a disturbed IL6-mediated acute phase response. The findings provide new insights and therapeutic options in sepsis.
... Heme Oxygenase-1 (HO-1) plays a significant role in the degradation of heme into biliverdin, iron, and carbon monoxide (CO) [5,6]. This enzyme, inducible by factors such as hyperoxia, hypoxia, bacterial lipopolysaccharides, and cytokines [7,8] and is upregulated in sepsis, leading to increased production of CO [9,10]. Such CO then binds to hemoglobin forming carboxyhemoglobin (COHb) which is easily measured with Arterial Blood Gases (ABGs) and may serve as an indirect marker of HO-1 activity and inflammation severity ( Figure S1) [6]. ...
Background: Sepsis-associated prognostic biomarkers are potentially useful for patient selection and stratification into sepsis trials. An elevated Carboxyhemoglobin (COHb) reflects heme degradation and, indirectly, red cell injury and is readily and freely available with Arterial Blood Gases (ABGs) measurements.
... Also, haem acts as a dangersignalling damage-associated molecular pattern which binds to toll-like receptor 4 [19], stimulates neutrophil activation [20], leads to neutrophil extracellular trap formation [21], and activates the alternative complement pathway [22]. Haemolysis is thought to contribute to the pathogenesis of sepsis [8,23] and severe COVID-19 [24], and hence has been proposed as a new treatment target [24]. Due to its pro-inflammatory properties, extracellular haemoglobin may also be associated with atherosclerotic plaque instability [25]. ...
There is growing evidence that inflammation impairs erythrocyte structure and function. We assessed the impact of mild systemic inflammation on erythrocyte fragility in three different settings. In order to investigate causation, erythrocyte osmotic fragility was measured in mice challenged with a live attenuated bacterial strain to induce low-grade systemic inflammation; a significant increase in erythrocyte osmotic fragility was observed. To gather evidence that systemic inflammation is associated with erythrocyte fragility in humans, two observational studies were conducted. First, using a retrospective study design, the relationship between reticulocyte-based surrogate markers of haemolysis and high-sensitivity C-reactive protein was investigated in 9292 healthy participants of the UK Biobank project. Secondly, we prospectively assessed the relationship between systemic inflammation (measured by the urinary neopterin/creatinine ratio) and erythrocyte osmotic fragility in a mixed population (n = 54) of healthy volunteers and individuals with long-term medical conditions. Both human studies were in keeping with a relationship between inflammation and erythrocyte fragility. Taken together, we conclude that mild systemic inflammation increases erythrocyte fragility and may contribute to haemolysis. Further research is needed to assess the molecular underpinnings of this pathway and the clinical implications in inflammatory conditions.
... The t3 group described here, with innate pathway signatures linked to acute inflammation and high mortality shares these features with the inflammopathic group reported by Sweeney and colleagues 8 . Finally, group t2 characterized by heme biosynthesis is consistent with the described immunometabolic endotypes and free heme has been shown to contribute to sepsis pathogenesis 6,48 . This study reinforces the generality of common sepsis endotypes, introduces to the best of our knowledge new cohorts of relatively understudied populations from West Africa and Southeast Asia, and identifies potential new therapeutic approaches to improving sepsis outcomes. ...
Background
Sepsis from infection is a global health priority and clinical trials have failed to deliver effective therapeutic interventions. To address complicating heterogeneity in sepsis pathobiology, and improve outcomes, promising precision medicine approaches are helping identify disease endotypes, however, they require a more complete definition of sepsis subgroups.
Methods
Here, we use RNA sequencing from peripheral blood to interrogate the host response to sepsis from participants in a global observational study carried out in West Africa, Southeast Asia, and North America (N = 494).
Results
We identify four sepsis subtypes differentiated by 28-day mortality. A low mortality immunocompetent group is specified by features that describe the adaptive immune system. In contrast, the three high mortality groups show elevated clinical severity consistent with multiple organ dysfunction. The immunosuppressed group members show signs of a dysfunctional immune response, the acute-inflammation group is set apart by molecular features of the innate immune response, while the immunometabolic group is characterized by metabolic pathways such as heme biosynthesis.
Conclusions
Our analysis reveals details of molecular endotypes in sepsis that support immunotherapeutic interventions and identifies biomarkers that predict outcomes in these groups.
... For instance, when subjected to a polymicrobial infection, mice with the haeme oxygenase-1 enzyme displayed increased tolerance (i.e. reduced tissue damage) compared to mice without this enzyme (Larsen et al., 2010). As ecologists are increasingly aware of the growing contribution of emerging infectious diseases to the loss of biodiversity (Daszak et al., 2000;Smith et al., 2006Smith et al., , 2009, investigating whether host resistance or tolerance exists in wildlife species of concern could be particularly important for predicting host-pathogen dynamics and informing conservation actions. ...
Testing for intraspecific variation for host tolerance or resistance in wild populations is important for informing conservation decisions about captive breeding, translocation, and disease treatment. Here, we test the importance of tolerance and resistance in multiple populations of boreal toads (Anaxyrus boreas boreas) against Batrachochytrium dendrobatidis (Bd), the amphibian fungal pathogen responsible for the greatest host biodiversity loss due to disease.
Boreal toads have severely declined in Colorado (CO) due to Bd, but toad populations challenged with Bd in western Wyoming (WY) appear to be less affected. We used a common garden infection experiment to expose post‐metamorphic toads sourced from four populations (2 in CO and 2 in WY) to Bd and monitored changes in mass, pathogen burden and survival for 8 weeks. We used a multi‐state modelling approach to estimate weekly survival and transition probabilities between infected and cleared states, reflecting a dynamic infection process that traditional approaches fail to capture.
We found that WY boreal toads are more tolerant to Bd infection with higher survival probabilities than those in CO when infected with identical pathogen burdens. WY toads also appeared more resistant to Bd with a higher probability of infection clearance and an average of 5 days longer to reach peak infection burdens. Our results demonstrate strong intraspecific differences in tolerance and resistance that likely contribute to why population declines vary regionally across this species.
Our multi‐state framework allowed us to gain inference on typically hidden disease processes when testing for host tolerance or resistance. Our findings demonstrate that describing an entire host species as ‘tolerant’ or ‘resistant’ (or lack thereof) is unwise without testing for intraspecific variation.
