Equol, a soybean metabolite with estrogen-like functions, decreases lipopolysaccharide-induced human neutrophil extracellular traps in vitro.

OBJECTIVE: Neutrophil extracellular traps (NETs) defend against acute infections. However, their overexpression causes organ failure during sepsis. Control of NET formation may improve the outcomes of patients with sepsis. Equol, a soybean isoflavone, is a female hormone analog, which prevents inflammation. We evaluated the effects of equol on NET formation in human neutrophils during inflammatory stimulation in vitro. METHODS: Healthy volunteers provided blood samples. An enzyme-linked immunosorbent assay (ELISA) assessed serum equol concentrations. NET formation in neutrophils was induced by lipopolysaccharide (LPS) treatment. ELISA quantified DNA-binding elastase, and immunostaining assessed NET formation. Reverse-transcription quantitative PCR and western blotting detected G-protein-coupled receptor 30 (GPR30) or peptidyl arginine deiminase 4 (PAD4) expression. Flow cytometry assessed neutrophil phagocytic ability with inactivated Escherichia coli. RESULTS: In neutrophils derived from males with low-serum equol levels (low-serum equol group), equol significantly decreased DNA-binding elastase levels and NET formation. Equol did not decrease NETs in neutrophils from males with high-serum equol levels. GPR30 expression of neutrophils was higher in the low-serum than in the high-serum equol group. PAD4 mRNA levels and nuclear PAD4 protein expression also decreased than the vehicle control in the low-serum equol group. Equol did not alter the phagocytic ability of neutrophils. In neutrophils from young females, equol had no inhibitory effect on NET formation. CONCLUSIONS: Equol decreases LPS-induced NET formation in neutrophils from males via inhibition of PAD4 expression. Our findings provide a rationale for investigating a new therapeutic approach using equol to control neutrophil activity during sepsis.

The role of death receptor signaling pathways in mouse Sertoli cell avoidance of apoptosis during LPS- and IL-18-induced inflammatory conditions.

Lipopolysaccharide (LPS) triggers infectious acute inflammation, and interleukin (IL)-18 is an inflammasome-mediated cytokine. We previously demonstrated that endogenous IL-18 induces testicular germ cell apoptosis during acute inflammation when plasma IL-18 levels are high. Additionally, high-dose recombinant IL-18 (rIL-18) induced Leydig cell apoptosis. The blood-testis barrier formed by Sertoli cells protects testicular germ cells from both exogenous and endogenous harmful substances. However, the impact of LPS and IL-18 on Sertoli cells remained unclear. We stimulated TM4 cells, a mouse Sertoli cell line, with LPS (200 or 1000 ng/mL) or rIL-18 (0.1-100 ng/mL) at levels that induced Leydig cell apoptosis in our previous study and assessed caspase 3 cleavage and the mRNA expression of inflammatory cytokines and markers of apoptotic pathways (Tnfr1, Fasl, Fas, Fadd) after stimulation. Il6 mRNA was increased by LPS stimulation. Tnfα mRNA was increased by 200 ng/mL LPS but not 1000 ng/mL LPS. Fas was increased, but Fasl was decreased, by LPS. LPS had little influence on Tnfr1 or Fadd mRNA expression and did not induce apoptosis. Il18 mRNA was not increased, and Il18r1 was significantly decreased following LPS treatment. Treatment with rIL-18 increased Il18r1 mRNA and induced inflammation, but decreased Tnfr1 and had little influence on apoptosis, as indicated by Tnfα, Fasl, Fas, Fadd and cleaved caspase 3. These results suggested that Sertoli cells do not easily undergo apoptosis despite strong inflammatory stimuli. Additionally, Sertoli cells may resist inflammation and play a larger role in protecting testicular homeostasis than other component cells of the testis.

Impact of frailty on long-term mortality in older patients receiving intensive care via the emergency department.

The aim of this study was to evaluate whether frailty was associated with 6-month mortality in older adults who were admitted to the intensive care unit (ICU) with an illness requiring emergency care. The investigation was a prospective, multi-center, observational study conducted among the ICUs of 17 participating hospitals. Patients ≥ 65 years of age who were admitted to the ICU directly from an emergency department visit were assessed to determine their baseline Clinical Frailty Scale (CFS) scores before the illness and were surveyed 6 months after admission. Among 650 patients included in the study, the median age was 79 years old, and overall mortality at 6 months was as low as 21%, ranging from 6.2% in patients with CFS 1 to 42.9% in patients with CFS ≥ 7. When adjusted for potential confounders, CFS score was an independent prognostic factor for mortality (one-point increase in CFS, adjusted risk ratio with 95% confidence interval 1.19 [1.09-1.30]). Quality of life 6 months after admission worsened as baseline CFS score increased. However, there was no association between total hospitalization cost and baseline CFS. CFS is an important predictor of long-term outcomes among critically ill older patients requiring emergent admission.

High Plasma tPAPAI-1C Levels May Be Related to a Poor Prognosis in Patients with Severe or Critical COVID-19: A Single-Center Retrospective Study.

Severe novel coronavirus disease 2019 (COVID-19) patients have a high incidence of thrombotic complications and mortality. The pathophysiology of coagulopathy involves fibrinolytic system impairment and vascular endothelial damage. This study examined coagulation and fibrinolytic markers as outcome predictors. In an observational study of 164 COVID-19 patients admitted to our emergency intensive care unit, hematological parameters on days 1, 3, 5, and 7 were retrospectively compared between survivors and nonsurvivors. Nonsurvivors had a higher APACHE II score, SOFA score, and age than survivors. Nonsurvivors also had a significantly lower platelet count and significantly higher plasmin/α2plasmin inhibitor complex (PIC), tissue plasminogen activator/plasminogen activator inhibitor-1 complex (tPAPAI-1C), D-dimer, and fibrin/fibrinogen degradation product (FDP) levels than survivors throughout the measurement period. The 7-day maximum or minimum values of the tPAPAI-1C, FDP, and D-dimer levels were significantly higher in nonsurvivors. A multivariate logistic regression analysis showed that the maximum tPAPAI-1C (OR = 1.034; 95% CI,1.014-1.061; p = 0.0041) was an independent factor affecting mortality, with an area under the curve (AUC) of 0.713 (optimum cut-off of 51 ng/mL; sensitivity, 69.2%; and specificity, 68.4%). COVID-19 patients with poor outcomes exhibit exacerbated coagulopathy with fibrinolysis inhibition and endothelial damage. Consequently, plasma tPAPAI-1C might be a useful predictor of the prognosis in patients with severe or critical COVID-19.

Stenotrophomonas maltophilia Bacteremia Associated With Severe COVID-19: Successful Treatment With Appropriate Antimicrobial Therapy.

Stenotrophomonas maltophilia, an opportunistic pathogen, can cause bacteremia in immunocompromised and debilitated patients. A 50-year-old man with severe coronavirus disease 2019 (COVID-19) was admitted to our hospital's intensive care unit where he underwent extracorporeal membrane oxygenation and ventilatory support. On day 25, he developed S. maltophilia bacteremia originating from an indwelling central venous catheter. After confirming susceptibility, trimethoprim-sulfamethoxazole (80 mg/400 mg) was administered thrice daily. Following improvement, he was weaned from ventilation, recovered sufficiently, and was discharged on day 53. To the best of our knowledge, this is the first report of a patient recovering after antimicrobial treatment for S. maltophilia bacteremia associated with severe COVID-19.

Effect of Tocilizumab Treatment on Patients with Coronavirus Disease 2019 and Bacteremia: A Retrospective Cohort Study.

INTRODUCTION: This study aimed to determine if tocilizumab treatment for coronavirus disease 2019 (COVID-19) increases bacteremia and suppresses fever and inflammatory reactants. METHODS: In this single-center, retrospective, observational study, all patients with COVID-19 admitted to our emergency intensive care unit from March 2020 to August 2021 were categorized into tocilizumab-treated and tocilizumab-naïve groups, and the incidence of bacteremia and other factors between the two groups were compared. Patients with bacteremia were further classified into tocilizumab-treated and tocilizumab-naïve groups to determine if fever and inflammatory reactants were suppressed. RESULTS: Overall, 144 patients were included in the study, 51 of whom received tocilizumab, which was administered on the day of admission. Further, of the 24 (16.7%) patients with bacteremia, 13 were in the tocilizumab-treated group. Results revealed a significant difference in the C-reactive protein level (p < 0.001) at the onset of bacteremia between the tocilizumab-treated group [median 0.42 mg/dL (0.27-0.44 mg/dL)] and the tocilizumab-naïve group [7.48 mg/dL (4.56-13.9 mg/dL)]. The median number of days from admission to onset of bacteremia was not significantly different between the tocilizumab-treated group [10 days (9-12 days)] and the tocilizumab-naïve group [9 days (7.5-11 days)] (p = 0.48). There was no significant difference in fever between the groups. Multivariate logistic analysis showed that tocilizumab treatment did not affect the probability of bacteremia. CONCLUSION: Treatment of patients with COVID-19 with tocilizumab does not increase the risk of bacteremia. Tocilizumab suppresses C-reactive protein levels but not fever. Therefore, careful monitoring of fever can reduce the risk of missed bacteremia.

Effect of Tocilizumab Treatment on Patients with Coronavirus Disease 2019 and Bacteremia: A Retrospective Cohort Study.

INTRODUCTION: This study aimed to determine if tocilizumab treatment for coronavirus disease 2019 (COVID-19) increases bacteremia and suppresses fever and inflammatory reactants. METHODS: In this single-center, retrospective, observational study, all patients with COVID-19 admitted to our emergency intensive care unit from March 2020 to August 2021 were categorized into tocilizumab-treated and tocilizumab-naïve groups, and the incidence of bacteremia and other factors between the two groups were compared. Patients with bacteremia were further classified into tocilizumab-treated and tocilizumab-naïve groups to determine if fever and inflammatory reactants were suppressed. RESULTS: Overall, 144 patients were included in the study, 51 of whom received tocilizumab, which was administered on the day of admission. Further, of the 24 (16.7%) patients with bacteremia, 13 were in the tocilizumab-treated group. Results revealed a significant difference in the C-reactive protein level (p < 0.001) at the onset of bacteremia between the tocilizumab-treated group [median 0.42 mg/dL (0.27-0.44 mg/dL)] and the tocilizumab-naïve group [7.48 mg/dL (4.56-13.9 mg/dL)]. The median number of days from admission to onset of bacteremia was not significantly different between the tocilizumab-treated group [10 days (9-12 days)] and the tocilizumab-naïve group [9 days (7.5-11 days)] (p = 0.48). There was no significant difference in fever between the groups. Multivariate logistic analysis showed that tocilizumab treatment did not affect the probability of bacteremia. CONCLUSION: Treatment of patients with COVID-19 with tocilizumab does not increase the risk of bacteremia. Tocilizumab suppresses C-reactive protein levels but not fever. Therefore, careful monitoring of fever can reduce the risk of missed bacteremia.

Inhaled hydrogen ameliorates endotoxin-induced bowel dysfunction.

Aim: Gastrointestinal dysmotility frequently occurs during sepsis and multiple organ failure, remaining a major cause of morbidity and mortality in critically ill patients. Previous studies have shown that hydrogen, a new therapeutic gas, can improve various organ damage associated with sepsis. In this study, we investigated the protective efficacies of inhaled hydrogen against lipopolysaccharide (LPS)-induced ileus. Methods: Sepsis was induced in rats and mice by a single i.p. injection of LPS at 15 mg/kg for mice and 5 mg/kg for rats. Four groups of rats and mice including sham/air, sham/hydrogen, LPS/air, and LPS/hydrogen were analyzed. Hydrogen (1.3%) was inhaled for 25 h beginning at 1 h prior to LPS treatment. Gastrointestinal transit was quantified and cytokine levels, as well as neutrophil extravasation, in the intestinal muscularis propria were determined. Results: Lipopolysaccharide challenge remarkably delayed gastrointestinal transit of non-absorbable dextran, associated with increased leukocyte recruitment and upregulation of pro-inflammatory cytokine mRNA expressions in the muscularis propria. Hydrogen significantly prevented LPS-induced bowel dysmotility and reduced leukocyte extravasation, as well as inhibition of inflammatory cytokine expression. In vitro analysis of cytokine levels after LPS treatment of cultured macrophages showed an increase of interleukin-10 by hydrogen regardless of the presence of nitric oxide. Conclusions: This study showed the protective effects of hydrogen inhalation on LPS-induced septic ileus through inhibition of inflammation in the muscularis propria. These inhibitory effects on the pro-inflammatory response may be partially derived from anti-inflammatory cytokine interleukin-10 induction.

Antithrombin III improved neutrophil extracellular traps in lung after the onset of endotoxemia.

BACKGROUND: Coagulation and inflammation are closely linked during acute inflammatory conditions, such as sepsis. Antithrombin (AT) is an anticoagulant that also has anti-inflammatory activities. The effects of therapeutically administering AT III after the onset of endotoxemia or sepsis were not clear. Here, we studied the effects of administering AT III after inducing lethal endotoxemia in mice. METHODS: Mice were injected intraperitoneally with lipopolysaccharide (LPS) to induce endotoxemia. AT III was administered 3 h later. We assessed survival and the severity of endotoxemia and quantified plasma cytokine levels and biochemical markers of liver and kidney function. In the lungs, we examined neutrophil accumulation, neutrophil extracellular traps, alveolar wall thickness, and chemokine (C-X-C motif) ligand 1 (cxcl-1), cxcl-2, and high mobility group box 1 expression. RESULTS: Administering AT III reduced the severity and mortality of LPS-induced endotoxemia as indicated by 24-h survival of 84% of the mice that received LPS + AT III and only 53% of mice given LPS alone (P < 0.05). AT III treatment attenuated several changes induced in the lungs by endotoxemia including cxcl-2 mRNA expression, high mobility group box 1 protein expression, neutrophil accumulation, alveolar septal thickening, and neutrophil extracellular trap formation. AT III did not decrease plasma cytokine levels or plasma urea nitrogen levels that were upregulated as a result of LPS-induced endotoxemia. CONCLUSIONS: Administration of AT III after the onset of endotoxemia improved outcomes in a mouse model. The attenuation of lung inflammation may have a large impact on mortality and morbidity. Because lung inflammation increases the likelihood of mortality from sepsis, AT III could be a useful agent in septic patients.

Donor pretreatment with carbon monoxide prevents ischemia/reperfusion injury following heart transplantation in rats.

Because inhaled carbon monoxide (CO) provides potent anti-inflammatory and antioxidant effects against ischemia reperfusion injury, we hypothesized that treatment of organ donors with inhaled CO would decrease graft injury after heart transplantation. Hearts were heterotopically transplanted into syngeneic Lewis rats after 8 hours of cold preservation in University of Wisconsin solution. Donor rats were exposed to CO at a concentration of 250 parts per million for 24 hours via a gas-exposure chamber. Severity of myocardial injury was determined by total serum creatine phosphokinase and troponin I levels at three hours after reperfusion. In addition, Affymetrix gene array analysis of mRNA transcripts was performed on the heart graft tissue prior to implantation. Recipients of grafts from CO-exposed donors had lower levels of serum troponin I and creatine phosphokinase; less upregulation of mRNA for interleukin-6, intercellular adhesion molecule-1, and tumor necrosis factor-α; and fewer infiltrating cells. Although donor pretreatment with CO altered the expression of 49 genes expressly represented on the array, we could not obtain meaningful data to explain the mechanisms by which CO potentiated the protective effects. Pretreatment with CO gas before organ procurement effectively protected cardiac grafts from ischemia reperfusion-induced injury in a rat heterotopic cardiac transplant model. A clinical report review indicated that CO-poisoned organ donors may be comparable to non-poisoned donors.

Case of 24-week Fetus Delivered from Mother on Life Support with Brain-death from Suicide Attempt: Ethical Issues Associated with Severe Complications.

Advances in critical care medicine have made it possible to sustain vital organ systems in brain-dead patients. One clinical scenario besides donor organ retrieval in which a benefit may be gained from continuing life support is pregnancy. A pregnant woman in her late 30's at 23 weeks gestation exhibiting worsening depression was referred to the Department of Psychiatry. One day after admission she attempted suicide by hanging and suffered a cardiopulmonary arrest. A fetal heart beat and fetal motion was confirmed immediately after resuscitation. Three days after admission, an emergency Cesarean section (CS) was performed because of her unstable hemodynamic situation. The baby was born and the mother died after delivery. The baby presented neurological complications. Such a case should be managed collaboratively among professional experts in several medical teams. Consensus and recommendations for the management of similar scenarios may also be adjusted.

Intraperitoneally administered, hydrogen-rich physiologic solution protects against postoperative ileus and is associated with reduced nitric oxide production.

BACKGROUND: Postoperative ileus, a transient impairment of bowel motility initiated by intestinal inflammation, is common after an abdominal operation and leads to increased hospital stays and costs. Hydrogen has potent anti-inflammatory and antioxidant properties and potential therapeutic value. Solubilized hydrogen may be a portable and practical means of administering therapeutic hydrogen gas. We hypothesized that intraperitoneal administration of hydrogen-rich saline would ameliorate postoperative ileus. METHODS: Ileus was induced via surgical manipulation in mice and rats. The peritoneal cavity was filled with 1.0 mL saline or hydrogen-rich saline (≥1.5-2.0 ppm) before closure of the abdominal incision. Intestinal transit was assessed 24 hours postoperatively. Inflammation was examined by quantitation of neutrophil extravasation and expression of proinflammatory markers. Nitric oxide production was assessed in cultured muscularis propria. RESULTS: Surgical manipulation resulted in a marked delay in intestinal transit and was associated with upregulation of proinflammatory cytokines and increased neutrophil extravasation. Bowel dysmotility, induced by surgical manipulation and inflammatory events, was significantly attenuated by intra-abdominal administration of hydrogen-rich saline. Nitric oxide production in the muscle layers of the bowel was inhibited by hydrogen treatment. CONCLUSION: A single intraperitoneal dose of hydrogen-rich saline ameliorates postoperative ileus by inhibiting the inflammatory response and suppressing nitric oxide production.

Hemorrhagic shock due to ruptured left and right gastric artery aneurysm.

Case: We report a case of hemorrhagic shock due to a ruptured gastric artery aneurysm successfully treated with transarterial embolization. A 72-year-old woman with cholangitis presented with hemoperitoneum following a ruptured aneurysm of the gastric artery. Outcome: Emergent computed tomography and angiography were carried out and the patient was found to have spontaneous bleeding from both branches of the left and right gastric arteries. Transcatheter embolization was carried out at the distal branch of both gastric arteries with a coil. The patient recovered well with no recurrent bleeding. Conclusions: Although rare, visceral artery rupture should be considered in the differential diagnosis of unexplained hemorrhagic shock with abrupt onset of hemoperitoneum. Computed tomography and angiography are useful tools for obtaining prompt and accurate localization of the bleeding points.

Successfully treated life-threatening upper gastrointestinal bleeding from fistula between gastroduodenal artery pseudoaneurysm and duodenum.

Case: An 85-year-old man was admitted to the hospital, underwent laparotomy, and was diagnosed with diffuse peritonitis due to perforation of gastric ulcer. Omental patch repair was carried out. After surgery, he suddenly vomited blood and manifested hypovolemic shock. An emergency upper gastrointestinal endoscopy was carried out immediately. However, the bleeding source was not visible. Dynamic-enhanced abdominal computed tomography showed a pseudoaneurysm of the gastroduodenal artery-communicating duodenal lumen with extravasation. Next, the patient underwent angiography for embolization. However, selective arterial embolization was not successful. Outcome: Finally, duodenotomy was carried out. The fistula between the pseudoaneurysm and duodenal lumen was directly ligated. An aneurysm could be clearly identified by previous findings. Conclusions: Gastroduodenal artery aneurysms are very uncommon but possibly lethal if they rupture. This life-threatening condition requires rapid diagnosis and treatment. Minimally invasive treatment is the preferred therapy for gastroduodenal artery aneurysm; however, acute care surgery should be considered without hesitation when conditions are critical.

Hydrogen inhalation protects against acute lung injury induced by hemorrhagic shock and resuscitation.

INTRODUCTION: Hemorrhagic shock followed by fluid resuscitation (HS/R) triggers an inflammatory response and causes pulmonary inflammation that can lead to acute lung injury (ALI). Hydrogen, a therapeutic gas, has potent cytoprotective, antiinflammatory, and antioxidant effects. This study examined the effects of inhaled hydrogen on ALI caused by HS/R. METHODS: Rats were subjected to hemorrhagic shock by withdrawing blood to lower blood pressure followed by resuscitation with shed blood and saline to restore blood pressure. After HS/R, the rats were maintained in a control gas of similar composition to room air or exposed to 1.3% hydrogen. RESULTS: HS/R induced ALI, as demonstrated by significantly impaired gas exchange, congestion, edema, cellular infiltration, and hemorrhage in the lungs. Hydrogen inhalation mitigated lung injury after HS/R, as indicated by significantly improved gas exchange and reduced cellular infiltration and hemorrhage. Hydrogen inhalation did not affect hemodynamic status during HS/R. Exposure to 1.3% hydrogen significantly attenuated the upregulation of the messenger RNAs for several proinflammatory mediators induced by HS/R. Lipid peroxidation was reduced significantly in the presence of hydrogen, indicating antioxidant effects. CONCLUSION: Hydrogen, administered through inhalation, may exert potent therapeutic effects against ALI induced by HS/R and attenuate the activation of inflammatory cascades.

Can carbon monoxide-poisoned victims be organ donors?

The increasing demand for organ allografts to treat end-stage organ failure has driven changes in traditional donor criteria. Patients who have succumbed to carbon monoxide (CO) poisoning, a common cause of toxicological mortality, are usually rejected as organ donors. To fulfill the increasing demand, selection criteria must be expanded to include CO-poisoned donors. However, the use of allografts exposed to high CO concentrations is still under debate. Basic research and literature review data suggest that patients with brain death caused by CO poisoning should be considered appropriate organ donors. Accepting organs from CO-poisoned victims could increase the number of potential donors and lower the death rate of patients on the waiting lists. This review and reported cases may increase awareness among emergency department physicians, as well as transplant teams, that patients dying of CO exposure may be acceptable organ donors.

IL18 production and IL18 promoter polymorphisms correlate with mortality in ICU patients.

BACKGROUND: Single nucleotide polymorphisms in the promoter of interleukin (IL)-18 (-607C/A and -137G/C) may affect the clinical course of inflammatory diseases. This study examined the relationship between the plasma IL18 levels, IL18 promoter polymorphism, and outcomes in the intensive care unit (ICU) setting. PATIENTS AND METHODS: Plasma IL18 levels, IL18 promoter genotype, clinical variables, including APACHE II score, and mortality were examined in 70 ICU patients. RESULTS: Plasma IL18 levels were significantly higher in patients who did not survive the ICU stay than in patients who survived, and were correlated with APACHE II score. When examined by IL18 promoter genotype, only patients with the -607CA genotype exhibited differences in IL18 expression between survivors and non-survivors. CONCLUSION: Plasma IL18 levels may predict outcome in patients with sepsis. IL18 promoter polymorphism, especially at -607, may increase IL18 production in some patients and might be useful in predicting the outcome of patients with sepsis in the ICU.

Supplementation of parenteral nutrition with fish oil attenuates acute lung injury in a rat model.

Fish oil rich in n-3 polyunsaturated fatty acids has diverse immunomodulatory properties and attenuates acute lung injury when administered in enternal nutrition. However, enteral nutrition is not always feasible. Therefore, we investigated the ability of parenteral nutrition supplemented with fish oil to ameliorate acute lung injury. Rats were infused with parenteral nutrition solutions (without lipids, with soybean oil, or with soybean oil and fish oil) for three days. Lipopolysaccharide (15 mg/kg) was then administered intratracheally to induce acute lung injury, characterized by impaired lung function, polymorphonuclear leukocyte recruitment, parenchymal tissue damage, and upregulation of mRNAs for inflammatory mediators. Administration of parenteral nutrition supplemented with fish oil prior to lung insult improved gas exchange and inhibited neutrophil recruitment and upregulation of mRNAs for inflammatory mediators. Parenteral nutrition supplemented with fish oil also prolonged survival. To investigate the underlying mechanisms, leukotriene B4 and leukotriene B5 secretion was measured in neutrophils from the peritoneal cavity. The neutrophils from rats treated with fish oil-rich parenteral nutrition released significantly more leukotriene B5, an anti-inflammatory eicosanoid, than neutrophils isolated from rats given standard parenteral nutrition. Parenteral nutrition with fish oil significantly reduced lipopolysaccharide-induced lung injury in rats in part by promoting the synthesis of anti-inflammatory eicosanoids.

Application of carbon monoxide for treatment of acute kidney injury.

Acute kidney injury in critically ill patients is common and associated with a substantial increase in morbidity and mortality. Even with aggressive medical care and renal replacement therapy, acute kidney injury remains a significant health care concern. Recent published reports offer new strategies for the prevention and amelioration of acute kidney injury using carbon monoxide. Although considered a toxic environmental gas, carbon monoxide has recently aroused scientific and clinical interest, as its beneficial effects and mechanisms of action have been substantially defined in various in vitro and in vivo experiments. The exogenous application of carbon monoxide can confer cytoprotection by modulating intracellular signaling pathways through its anti-inflammatory, anti-apoptotic, vasodilative, antithrombotic and antiproliferative properties. Thus, evidence is accumulating to support the notion of carbon monoxide treatment for acute kidney disease. In this review, we focus on the extensively analyzed advantageous value of treatment with inhaled/soluble carbon monoxide in the context of kidney injury. Mechanisms such as signaling pathways, as well as an expanded view regarding toxicity and side-effects, are described broadly. In addition, we discuss the clinical applicability of carbon monoxide as a promising therapeutic strategy for the treatment of patients with acute kidney disease based on translating basic experimental findings into clinical application.