Increase of HO-1 Expression in Critically Ill COVID-19 Patients Is Associated with Poor Prognosis and Outcome

Detsika, Maria G.; Nikitopoulou, Ioanna; Veroutis, Dimitris; Vassiliou, Alice G.; Jahaj, Edison; Tsipilis, Stamatios; Athanassiou, Nikolaos; Gakiopoulou, Hariklia; Gorgoulis, Vassilis G.; Dimopoulou, Ioanna; Orfanos, Stylianos E.; Kotanidou, Anastasia

doi:10.3390/antiox11071300

Cited by 8 publications

(9 citation statements)

References 24 publications

(25 reference statements)

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“…One human sepsis study reported that high HO-1 levels were associated with sepsis severity and low survival [ 7 ]. Increased HO-1 expression has been found in severe-to-critically ill patients with COVID-19, with a poor survival prognosis [ 8 ]. However, the role of heme catabolism in COVID-19-related sepsis remains unknown.…”

Section: Introductionmentioning

confidence: 99%

Association between heme oxygenase one and sepsis development in patients with moderate-to-critical COVID-19: a single-center, retrospective observational study

Chen

Tzeng

et al. 2022

Eur J Med Res

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Background Heme oxygenase one (HO-1) is considered a poor prognostic factor for survival in patients with severe-to-critical coronavirus disease (COVID-19), but the clinical correlation between heme catabolism biomarkers and COVID-19-related sepsis is unknown. The etiopathogenetic hypothesis of HO-1 response during sepsis in patients with poor prognosis should be clarified. This study aimed to investigate sepsis development within 48 h following moderate-to-critical COVID-19 and examined heme/HO-1 catabolism biomarkers associated with sepsis. We also studied the HO-1 and traditional prognostic factors for predicting survival in patients with COVID-19. Methods This retrospective observational study included patients unvaccinated for COVID-19 with moderate-to-critical COVID-19 (n = 156) who had been admitted to Taipei Tzu Chi Hospital in 2021. All COVID-19 patients were diagnosed by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcriptase polymerase chain reaction. For analysis of heme catabolism in SARS-CoV-2-induced sepsis, we excluded patients with co-infection and severe anemia. Heme catabolism biomarkers were compared between groups of patients with COVID-19 and sepsis (sepsis) and those with COVID-19 without sepsis (no sepsis), and a control group comprising 100 healthy individuals. All clinical and laboratory data were collected retrospectively and blood specimens were collected from Biobank. Multivariable logistic regression analysis was used to compare all variables between the sepsis and no-sepsis groups. Cox regression analysis was used to determine predictors of survival in patients with COVID-19. Results There were 71 and 85 patients with and without sepsis, respectively. Heme and HO-1 levels differed significantly between the sepsis, no sepsis, and control groups. In multivariate analysis, confusion, blood urea nitrogen, respiration, blood pressure in patients aged > 65 years (CURB-65) (adjusted odds ratio [aOR] 5.331, 95% confidence interval [CI] 2.587–10.987; p < 0.001), albumin (aOR 0.139, 95% CI 0.003–0.636; p = 0.01), d-dimer (aOR 1.001, 95% CI 1.000–1.002; p = 0.032), and HO-1 (aOR 1.116, 95% CI 1.055–1.180; p < 0.001) were significantly associated with 48-h sepsis episodes after adjusting for other confounding factors. HO-1 levels were also significantly associated with 48-h Sequential Organ Failure Assessment Score (SOFA) scores. However, HO-1 did not significantly increase the hazard of in-hospital mortality in moderate-to-critical COVID-19 by Cox regression analysis. Conclusions HO-1 levels increased with sepsis development within 48 h of admission for COVID-19 after adjusting for other risk factors, but no significant association was observed between HO-1 and COVID-19 mortality. We suppose that HO-1 may have protective effect in early sepsis, but further clinical multicenter prospective studies are needed.

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Section: Introductionmentioning

confidence: 99%

Association between heme oxygenase one and sepsis development in patients with moderate-to-critical COVID-19: a single-center, retrospective observational study

Chen

Tzeng

et al. 2022

Eur J Med Res

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“…A recent study demonstrated increased HMOX mRNA expression in circulating leukocytes in COVID-19 patients. 39 Other study which measured circulating HO-1 levels in blood from these patients also demonstrated upregulation of HO-1 levels in a population of eight patients. 19 More recently, a larger study encompassing 64 patients demonstrated that HO-1 is consistently associated with clinical and laboratory markers of disease severity, and that its measurement could refine prediction models for ICU admission.…”

Section: Discussionmentioning

confidence: 80%

Association of heme-oxygenase 1, hemopexin, and heme levels with markers of disease severity in COVID-19

Lima

Moraes

Barbosa

et al. 2023

Exp Biol Med (Maywood)

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Heme-oxygenase 1 (HO-1) is an enzyme with well-known anti-inflammatory and antioxidant properties, whose levels have been previously associated with disease severity in the context of sterile and infectious diseases. Moreover, the heme/HO-1 pathway has been associated with prothrombotic changes in other diseases. Accordingly, the potential of modulating HO-1 levels for the treatment of COVID-19 was extensively speculated during the COVID-19 pandemic, but very few actual data were generated. The aim of our study was to explore the association of HO-1, heme, and hemopexin (HPX) levels with COVID-19 severity and with markers of inflammation and coagulation activation. The study was conducted in 30 consecutive patients with COVID-19 admitted due to hypoxemia, and 30 healthy volunteers matched by sex, age, and geographic region. HO-1 and HPX levels were measured by enzyme immunoassay (ELISA) and heme levels were measured by a colorimetric method. A comprehensive panel of coagulation and fibrinolysis activation was also used. Patients with COVID-19 presented increased levels of HO-1 when compared to controls (5741 ± 2696 vs 1953 ± 612 pg/mL, respectively, P < 0.0001), as well as a trend toward increased levels of HPX (3.724 ± 0.880 vs 3.254 ± 1.022 mg/mL, respectively; P = 0.06). In addition, HO-1 and HPX levels reduced from admission to day + 4. HO-1 levels were associated with duration of intensive care unit stay and with several markers of coagulation activation. In conclusion, modulation of HO-1 could be associated with the prothrombotic state observed in COVID-19, and HO-1 could also represent a relevant biomarker for COVID-19. New independent studies are warranted to explore and expand these findings.

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“…Nrf2 is a transcription factor that binds to the antioxidant response element (ARE) and activates the expression of various antioxidant genes, such as HO-1 and NQO1 [ 47 – 49 ]. HO-1 is an enzyme that catalyzes the degradation of heme, a pro-oxidant molecule known as biliverdin, carbon monoxide and iron, which have anti-inflammatory, anti-apoptotic and cytoprotective effects [ 50 ]. NQO1 can reduce quinones to hydroquinone, which can be further conjugated with glutathione and excreted from the cells [ 51 , 52 ].…”

Section: Discussionmentioning

confidence: 99%

Hesperidin ameliorates H2O2-induced bovine mammary epithelial cell oxidative stress via the Nrf2 signaling pathway

Huang,

Liu,

Peng

et al. 2024

J Animal Sci Biotechnol

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Background Hesperidin is a citrus flavonoid with anti-inflammatory and antioxidant potential. However, its protective effects on bovine mammary epithelial cells (bMECs) exposed to oxidative stress have not been elucidated. Results In this study, we investigated the effects of hesperidin on H2O2-induced oxidative stress in bMECs and the underlying molecular mechanism. We found that hesperidin attenuated H2O2-induced cell damage by reducing reactive oxygen species (ROS) and malondialdehyde (MDA) levels, increasing catalase (CAT) activity, and improving cell proliferation and mitochondrial membrane potential. Moreover, hesperidin activated the Keap1/Nrf2/ARE signaling pathway by inducing the nuclear translocation of Nrf2 and the expression of its downstream genes NQO1 and HO-1, which are antioxidant enzymes involved in ROS scavenging and cellular redox balance. The protective effects of hesperidin were blocked by the Nrf2 inhibitor ML385, indicating that they were Nrf2 dependent. Conclusions Our results suggest that hesperidin could protect bMECs from oxidative stress injury by activating the Nrf2 signaling pathway, suggesting that hesperidin as a natural antioxidant has positive potential as a feed additive or plant drug to promote the health benefits of bovine mammary. Graphical Abstract

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Increase of HO-1 Expression in Critically Ill COVID-19 Patients Is Associated with Poor Prognosis and Outcome

Cited by 8 publications

References 24 publications

Association between heme oxygenase one and sepsis development in patients with moderate-to-critical COVID-19: a single-center, retrospective observational study

Association between heme oxygenase one and sepsis development in patients with moderate-to-critical COVID-19: a single-center, retrospective observational study

Association of heme-oxygenase 1, hemopexin, and heme levels with markers of disease severity in COVID-19

Hesperidin ameliorates H2O2-induced bovine mammary epithelial cell oxidative stress via the Nrf2 signaling pathway

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