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[Image: see text] Acute respiratory distress syndrome (ARDS) is one of the critical stages of COVID-19, leading to lung injury and hemolysis. Dysfunctional hemoglobin (Hb) suffers low-level oxygenation, overloaded iron, and down-regulation of hemeoxygenase-1 (HO-1), representing potential therapeutic interventions. This Viewpoint outlines the Hb–HO-1 system as a host-cell target, and proposes possible therapies, including iron chelation and CO therapies, against COVID-19 with ARDS.

Background. Hemeoxygenase-1 (HO-1) is an essential enzyme in heme catabolism and has been proposed as a biomarker of lung disease prognosis. We modified a commercial HO-1 enzyme-linked immunosorbent assay (ELISA) kit to achieve higher sensitivity and evaluated if serum HO-1 could be a biomarker to predict the prognosis of acute respiratory distress syndrome (ARDS) patients.Methods. Serum samples were collected from 15 healthy volunteers to validate the modified ELISA. In the 22 patients with ARDS who were enrolled, serum HO-1 was measured upon diagnosis (D0) and at 7 days after diagnosis (D7).Results. The serum HO-1 concentration could be measured in all healthy volunteers. The intra- and interassay tests and the percentage recovery test were acceptable. Compared with normal control subjects, patients with ARDS had significantly higher D0 HO-1 concentrations (75.4 ng/mL versus 31.7 ng/mL,P<0.001). The 28-day survival was significantly better in patients with low D0 HO-1 (P=0.016). Nonsurvivors had significantly higher D0 and D7 HO-1 concentrations than survivors (P<0.05).Conclusion. Serum HO-1 may be a useful biomarker to predict the prognosis of patients with ARDS.

Background. Serum hemeoxygenase-1 (HO-1) has been proposed to be a biomarker of lung disease activity and prognosis. The present study aimed at evaluating whether HO-1 could be a useful marker for evaluating disease activity and predicting prognosis in patients with interstitial pneumonia (IP). Materials and Methods. Serum HO-1 levels of newly diagnosed or untreated patients with IP were measured at hospitalization. We evaluated the relationships between serum HO-1 and other serum biomarkers, high resolution CT (HRCT) findings, and hospital mortality. Results. Twenty-eight patients with IP, including 14 having an acute exacerbation (AE) and 14 not having an AE, were evaluated. The patients having an AE had significantly higher HO-1 levels than those not having an AE (53.5 ng/mL vs. 24.1 ng/mL; p<0.001), and the best cut-off level to discriminate between having an AE or not having an AE was 41.6 ng/mL. Serum HO-1 levels were positively correlated with serum levels of surfactant protein-D (r=0.66, p<0.001) and the ground glass opacity score (calculated from HRCT; r=0.40, p=0.036). Patients who subsequently died in hospital had presented with significantly higher HO-1 levels than those who did not die in hospital (64.8 ng/mL vs. 32.0 ng/mL; p=0.009). Conclusion. Serum HO-1 may serve as a useful biomarker for detecting AE or predicting hospital mortality in patients with IP.

Hemeoxygenase-1 induction in response to adverse circulatory conditions is protective. Our recent study has shown that administration of sirtinol attenuates hepatic injury in male Sprague-Dawley rats after trauma-hemorrhage; however, the mechanism by which sirtinol produces the salutary effects remains unknown. We hypothesized that sirtinol administration in male Sprague-Dawley rats after trauma-hemorrhage decreases cytokine production and protects against lung injury through a hemeoxygenase-1 related pathway.Male Sprague-Dawley rats (n = 8 per group) underwent trauma-hemorrhage (mean arterial blood pressure 40 mm Hg for 90 min, then resuscitation). A single dose of sirtinol (1 mg/kg of body weight) with or without a hemeoxygenase enzyme inhibitor (chromium-mesoporphyrin) or vehicle was administered IV during resuscitation. Twenty-four hours thereafter, myeloperoxidase activity (a marker of neutrophil sequestration) and tumor necrosis factor alpha, interleukin-6, and interleukin-10 levels in the lung, protein concentrations in bronchoalveolar lavage fluid and tissue histology were measured. Lung hemeoxygenase-1 protein level was also determined.In the sirtinol-treated rats subjected to trauma-hemorrhage, there were significant improvements in lung myeloperoxidase activity (4.68 +/- 0.31 vs 9.36 +/- 1.03 U/mg protein, P0.05), tumor necrosis factor alpha levels (710.7 +/- 28 vs 1288 +/- 40.69 pg/mg protein, P0.05), interleukin-6 levels (343.6 +/- 18.41 vs 592.7 +/- 22.3 pg/mg protein, P0.05), and protein concentrations (303.8 +/- 24.54 vs 569.6 +/- 34.82 microg/mL, P0.05) and lesser damage in histology. There was no statistically significant difference in interleukin-10 levels in the lung between sirtinol-treated trauma-hemorrhaged rats and vehicle-treated trauma-hemorrhaged rats (842.5 +/- 54.18 vs 756.2 +/- 41.34 pg/mg protein, respectively). Lung hemeoxygenase-1 protein levels were increased in rats receiving sirtinol treatment as compared with vehicle-treated trauma-hemorrhaged rats (5.18 +/- 0.25 vs 2.70 +/- 0.16, P0.05). Administration of the hemeoxygenase inhibitor chromium-mesoporphyrin prevented the sirtinol-induced attenuation of shock-induced lung damage.The salutary effects of sirtinol administration on attenuation of lung inflammation after trauma-hemorrhage are mediated via upregulation of hemeoxygenase-1 expression.

Objectives The renin-angiotensin system (RAS) is thought to play a major role in the pathophysiology of de-novo restenotic lesions and in-stent restenosis after percutaneous coronary intervention (PCI). Heme oxygenase-1 (HO-1), is thought to beneficially influence these processes. We examined the effect of pharmacologic as well as genetic RAS interactions on restenosis in a large population of consecutive patients undergoing PCI, and evaluated possible gene-gene interactions in both systems. Methods The GENDER project is a multicenter prospective follow-up study, including 3146 patients after successful PCI. Genotyping in these patients was performed for the ACE gene insertion/deletion, the angiotensinogen 235Met/Thr, T174M and A(-6)G, the angiotensin-II type 1 receptor (AT1R) 1166A/C and T81OA, the angiotensin-II type 2 receptor (AT2R) 1675G/A and 3123A polymorphisms and the length polymorphism in the HO-1 promoter region. Results A total of 3104 patients were followed for 10 months. In 2975 patients at least one of the nine genotypes could be determined. The AT1R 1166 CC genotype showed a significant association with TVR; the other polymorphisms did not. RAS-inhibitory drugs were not associated with the incidence of TVR, nor did they interact with any of the investigated polymorphisms. Patients with the ACE I/I polymorphism showed a trend towards a better outcome if they had a short number of repeats in the HO-1 promoter. This relationship was inversely present in carriers of the ACE D/D polymorphism. Conclusion We could only establish a role for the AT1R 1166A/C polymorphism in restenosis after PCI. However, significant gene-gene interaction was suggested for the ACE gene and the HO-1 promotor. The RAS and HO-1 relation in restenosis merits further investigation. Pharmacogenetics and Genomics 16:331-337 (c) 2006 Lippincott Williams & Wilkins.

Recurring insulin-induced hypoglycemia (RIIH) often occurs during therapeutic management of insulin dependent diabetes mellitus. There is evidence that both cardiac and adrenergic sensitivity are altered in type 1 diabetics. Controversy currently exists in literature as to the ability of insulin to promote hypertension. Could insulin promote adverse pressor effects, if so under what conditions and through what mechanism? Thus, the current study was performed to evaluate the hypothesis that hypoglycemia promotes hypertension via an increase in Heme oxygenase-1 (HO-1). Male Sprague Dawley rats (200 – 225g) were treated for 2 weeks with varying doses of subcutaneous insulin injections (1, 3, 5, 7, and 9 U/kg body weight) and fed on normal chow or zinc diet (1mM) for 2 weeks. Tail-cuff blood pressure, food/water intake and blood glucose states were monitored daily. A dose dependent decrease in blood glucose was observed. Blood pressure was significantly elevated in rats treated with 7U/Kg dose as compared to ...

Induction of hemeoxygenase-1 (HO-1) lowers blood pressure and reduces organ damage in hypertensive animal models; however, a potential protective role for HO-1 induction against diabetic-induced glomerular injury remains unclear. We hypothesize that HO-1 induction will protect against diabetes-induced glomerular injury by maintaining glomerular integrity and inhibiting renal apoptosis, inflammation, and oxidative stress. Diabetes was induced with streptozotocin in spontaneously hypertensive rats (SHR) as a model where the coexistence of hypertension and diabetes aggravates the progression of diabetic renal injury. Control and diabetic SHR were randomized to receive vehicle or the HO-1 inducer cobalt protoporphyrin (CoPP). Glomerular albumin permeability was significantly greater in diabetic SHR compared with control, consistent with an increase in apoptosis and decreased glomerular nephrin and α3β1-integrin protein expression in diabetic SHR. CoPP significantly reduced albumin permeability and apoptosis and restored nephrin and α3β1-integrin protein expression levels in diabetic SHR. Glomerular injury in diabetic SHR was also associated with increases in NF-κB-induced inflammation and oxidative stress relative to vehicle-treated SHR, and CoPP significantly blunted diabetes-induced increases in glomerular inflammation and oxidative stress in diabetic SHR. These effects were specific to exogenous stimulation of HO-1, since incubation with the HO inhibitor stannous mesoporphyrin alone did not alter glomerular inflammatory markers or oxidative stress yet was able to prevent CoPP-mediated decreases in these parameters. These data suggest that induction of HO-1 reduces diabetic induced-glomerular injury and apoptosis and these effects are associated with decreased NF-κB-induced inflammation and oxidative stress.

The complement cascade is activated and contributes to brain damage after intracerebral hemorrhage (ICH). The present study investigated ICH-induced brain damage in complement C3-deficient mice.