Endotoxin-Induced Mortality Is Related to Increased Oxidative Stress and End-Organ Dysfunction, Not Refractory Hypotension, in Heme Oxygenase-1–Deficient Mice

Wiesel, Philippe; Patel, Anand; DiFonzo, Nicole; Marria, Pooja B.; Sim, Chäng U.; Pellacani, Andrea; Maemura, Koji; LeBlanc, Brian W.; Marino, Kathryn; Doerschuk, Claire M.; Yet, Shaw Fang; Lee, Mu En; Perrella, Mark A.

doi:10.1161/01.cir.102.24.3015

Cited by 178 publications

(148 citation statements)

References 29 publications

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“…HO-1 and its metabolites have been shown to exhibit beneficial anti-inflammatory properties in pure inflammatory models of disease such as endotoxemia (38). However, inhibition of the inflammatory response to bacterial infection by the HO-1 system might disrupt the ability of the immune system to eliminate invading bacteria.…”

Section: Ho-1 Impairs Host Defense Of Macrophages Against B Pseudomamentioning

confidence: 99%

Heme Oxygenase-1 and Carbon Monoxide PromoteBurkholderia pseudomalleiInfection

Stolt

Schmidt

Sayfart

et al. 2016

The Journal of Immunology

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The environmental bacterium and potential biothreat agent Burkholderia pseudomallei causes melioidosis, an often fatal infectious disease. Increased serum bilirubin has been shown to be a negative predictive factor in melioidosis patients. We therefore investigated the role of heme oxygenase-1 (HO-1), which catalyzes the degradation of heme into the bilirubin precursor biliverdin, ferrous iron, and CO during B. pseudomallei infection. We found that infection of murine macrophages induces HO-1 expression, involving activation of several protein kinases and the transcription factor nuclear erythroid-related factor 2 (Nrf2). Deficiency of Nrf2 improved B. pseudomallei clearance by macrophages, whereas Nrf2 activation by sulforaphane and tert-butylhydroquinone with subsequent HO-1 induction enhanced intracellular bacterial growth. The HO-1 inducer cobalt protoporphyrin IX diminished proinflammatory cytokine levels, leading to an increased bacterial burden in macrophages. In contrast, HO-1 gene knockdown reduced the survival of intramacrophage B. pseudomallei. Pharmacological administration of cobalt protoporphyrin IX to mice resulted in an enhanced bacterial load in various organs and was associated with higher mortality of intranasally infected mice. The unfavorable outcome of B. pseudomallei infection after HO-1 induction was associated with higher serum IL-6, TNF-α, and MCP-1 levels but decreased secretion of IFN-γ. Finally, we demonstrate that the CO-releasing molecule CORM-2 increases the B. pseudomallei load in macrophages and mice. Thus, our data suggest that the B. pseudomallei–mediated induction of HO-1 and the release of its metabolite CO impair bacterial clearance in macrophages and during murine melioidosis.

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Section: Ho-1 Impairs Host Defense Of Macrophages Against B Pseudomamentioning

confidence: 99%

Heme Oxygenase-1 and Carbon Monoxide PromoteBurkholderia pseudomalleiInfection

Stolt

Schmidt

Sayfart

et al. 2016

The Journal of Immunology

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“…These animals display severe growth retardation, anemia, iron deposition in the kidneys and liver, and evidence of chronic inflammation in a variety of organs. In other investigations involving HO-1 null mutant mice the animals have been demonstrated to be more susceptible to: 1) renovascular-related hypertension, renal failure, and cardiac hypertrophy (102), 2) endotoxin-mediated lethality (103), and 3) right ventricular dilation and infarction secondary to chronic hypoxia (104). Collectively, the in vitro, in vivo, and gene deletion studies outlined above provide compelling evidence regarding the broad cytoprotective role of HO-1 in clinically relevant forms of cellular and tissue injury.…”

Section: Hsp 32 (Heme Oxygenase)mentioning

confidence: 99%

Heat shock response and acute lung injury☆

Wheeler

Wong

2007

Free Radical Biology and Medicine

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All cells respond to stress through the activation of primitive, evolutionarily conserved genetic programs that maintain homeostasis and assure cell survival. Stress adaptation, which is known in the literature by a myriad of terms, including tolerance, desensitization, conditioning, and reprogramming, is a common paradigm found throughout nature, in which a primary exposure of a cell or organism to a stressful stimulus (e.g., heat) results in an adaptive response by which a second exposure to the same stimulus produces a minimal response. More interesting is the phenomenon of cross-tolerance, by which a primary exposure to a stressful stimulus results in an adaptive response whereby the cell or organism is resistant to a subsequent stress that is different from the initial stress (i.e. exposure to heat stress leading to resistance to oxidant stress). The heat shock response is one of the more commonly described examples of stress adaptation and is characterized by the rapid expression of a unique group of proteins collectively known as heat shock proteins (also commonly referred to as stress proteins). The expression of heat shock proteins is well described in both whole lungs and in specific lung cells from a variety of species and in response to a variety of stressors. More importantly, in vitro data, as well as data from various animal models of acute lung injury, demonstrate that heat shock proteins, especially Hsp27, Hsp32, Hsp60, and Hsp70 have an important cytoprotective role during lung inflammation and injury.

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“…Wiesel et al 12 found that HO-1 knockout mice show increased end-organ damage and death. Pae et al 13 also reported that HO-1 has protective properties in allergic inflammation, and other researchers *The first two authors contributed equally to this work.…”

Section: Introduction Imentioning

confidence: 99%

Anti-Inflammatory Effect of Heme Oxygenase-1 TowardPorphyromonas gingivalisLipopolysaccharide in Macrophages Exposed to Gomisins A, G, and J

Ryu

Park

Kim

et al. 2011

Journal of Medicinal Food

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Periodontitis, a chronic inflammatory periodontal disease that develops from gingivitis, is caused by periodontal pathogenic bacteria such as Porphyromonas gingivalis. Recent studies have focused on the antioxidant, anti-human immunodeficiency virus, anticarcinogenic, and anti-inflammatory properties of gomisins. However, the anti-inflammatory activities of gomisin plants through heme oxygenase-1 (HO-1) signals remain poorly defined. We found that gomisins' antiinflammatory activity occurs via the induction of HO-1 expression. Gomisins G and J inhibit the production of the proinflammatory cytokines tumor necrosis factor-a, interleukin-1b, and interleukin-6 and also block nuclear factor-jB activation in Raw264.7 cells stimulated with P. gingivalis lipopolysaccharide. Furthermore, pro-inflammatory cytokine production is inhibited through the induction of HO-1 expression. HO-1 expression is induced by all gomisins, but their anti-inflammatory activity via HO-1 signaling is observed with gomisins G and J, and not A. We found that gomisins G and J extracted from Schisandria chinensis can inhibit the P. gingivalis lipopolysaccharide induced-inflammatory responses in Raw264.7 cells.KEY WORDS: gomisins A, G, and J heme oxygenase-1 nuclear factor E2-related factor 2 Porphyromonas gingivalis lipopolysaccharide pro-inflammatory cytokines

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Endotoxin-Induced Mortality Is Related to Increased Oxidative Stress and End-Organ Dysfunction, Not Refractory Hypotension, in Heme Oxygenase-1–Deficient Mice

Abstract: These data suggest that the increased mortality during endotoxemia in HO-1(-/-) mice is related to increased oxidative stress and end-organ (renal and hepatic) damage, not to refractory hypotension.

Cited by 178 publications

References 29 publications

Heme Oxygenase-1 and Carbon Monoxide PromoteBurkholderia pseudomalleiInfection

Heme Oxygenase-1 and Carbon Monoxide PromoteBurkholderia pseudomalleiInfection

Heat shock response and acute lung injury☆

Anti-Inflammatory Effect of Heme Oxygenase-1 TowardPorphyromonas gingivalisLipopolysaccharide in Macrophages Exposed to Gomisins A, G, and J

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