Cotransfection of heme oxygenase-1 prevents the acute inflammation elicited by a second adenovirus

McCarter, Sarah D.; Scott, Jeffrey R.; Lee, P J; Zhang, X; Choi, Augustine M.K.; McLean, Carolyn A.; Badhwar, Amit; Dungey, Alison A.; Bihari, Aurelia; Harris, Kenneth A.; Potter, Richard F.

doi:10.1038/sj.gt.3302063

Cited by 11 publications

(4 citation statements)

References 44 publications

(65 reference statements)

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“…In fact, since the initial indication that HO‐1 protected against a pleural model of inflammation (Willis et al ., 1996), substantial experimental evidence has been accumulated to show that inhibition of heme oxygenase activity exacerbates the inflammatory response while prior induction of HO‐1 significantly reduces inflammation (Wagener et al ., 2003). A striking example of this phenomenon is found in a report describing the effects of adenoviral transfection of the HO‐1 gene (McCarter et al ., 2003), whereby the HO‐1 adenovirus did not elicit the acute inflammation usually associated with this type of transfection and could also prevent the inflammation caused by a second adenovirus. The exact mechanisms underlying this effect are not clear, although hypotheses have been advanced based on the known characteristics of the products of heme oxygenase activity.…”

Section: Introductionmentioning

confidence: 85%

Carbon monoxide‐releasing molecules (CO‐RMs) attenuate the inflammatory response elicited by lipopolysaccharide in RAW264.7 murine macrophages

Sawle

Foresti

Mann

et al. 2005

British J Pharmacology

358

310

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1 The enzyme heme oxygenase-1 (HO-1) is a cytoprotective and anti-inflammatory protein that degrades heme to produce biliverdin/bilirubin, ferrous iron and carbon monoxide (CO). The antiinflammatory properties of HO-1 are related to inhibition of adhesion molecule expression and reduction of oxidative stress, while exogenous CO gas treatment decreases the production of inflammatory mediators such as cytokines and nitric oxide (NO). CO-releasing molecules (CO-RMs) are a novel group of substances identified by our group that are capable of modulating physiological functions via the liberation of CO. We aimed in this study to examine the potential anti-inflammatory characteristics of CORM-2 and CORM-3 in an in vitro model of lipopolysaccharide (LPS)-stimulated murine macrophages. 2 Stimulation of RAW264.7 macrophages with LPS resulted in increased expression of inducible NO synthase (iNOS) and production of nitrite. CORM-2 or CORM-3 (10-100 mM) reduced nitrite generation in a concentration-dependent manner but did not affect the protein levels of iNOS. CORM-3 also decreased nitrite levels when added 3 or 6 h after LPS exposure. 3 CORM-2 or CORM-3 did not cause any evident cytotoxicity and produced an increase in HO-1 expression and heme oxygenase activity; this effect was completely prevented by the thiol donor N-acetylcysteine. 4 CORM-3 also considerably reduced the levels of tumor necrosis factor-a, another mediator of the inflammatory response. 5 The inhibitory effects of CORM-2 and CORM-3 were not observed when the inactive compounds, which do not release CO, were coincubated with LPS. 6 These results indicate that CO liberated by CORM-2 and CORM-3 significantly suppresses the inflammatory response elicited by LPS in cultured macrophages and suggest that CO carriers can be used as an effective strategy to modulate inflammation.

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Section: Introductionmentioning

confidence: 85%

Carbon monoxide‐releasing molecules (CO‐RMs) attenuate the inflammatory response elicited by lipopolysaccharide in RAW264.7 murine macrophages

Sawle

Foresti

Mann

et al. 2005

British J Pharmacology

358

310

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“…The pathogenesis of most infectious conditions is mediated by oxidative stress, and as a result, induction of HO-1 activity protects the host organism against pathogen-induced disease (Otterbein et al 1995;McCarter et al 2003;Sahni et al 2005). Studies examining direct effects of inhibiting mammalian HO activity on infectivity and virulence of pathogens are lacking.…”

Section: Ho Activity In Infectionsmentioning

confidence: 99%

Inhibitors of the heme oxygenase – carbon monoxide system: on the doorstep of the clinic?

Kinobe

Dercho

Nakatsu

2008

Can. J. Physiol. Pharmacol.

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The past decade has seen substantial developments in our understanding of the physiology, pathology, and pharmacology of heme oxygenases (HO), to the point that investigators in the field are beginning to contemplate therapies based on administration of HO agonists or HO inhibitors. A significant amount of our current knowledge is based on the judicious application of metalloporphyrin inhibitors of HO, despite their limitations of selectivity. Recently, imidazole-based compounds have been identified as potent and more selective HO inhibitors. This 'next generation' of HO inhibitors offers a number of desirable characteristics, including isozyme selectivity, negligible effects on HO protein expression, and physicochemical properties favourable for in vivo distribution. Some of the applications of HO inhibitors that have been suggested are treatment of hyperbilirubinemia, neurodegenerative disorders, certain types of cancer, and bacterial and fungal infections. In this review, we address various approaches to altering HO activity with a focus on the potential applications of second-generation inhibitors of HO.

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“…The safety of adenovirus vectors was brought into question after acute inflammation resulted in the death of a volunteer in a 1999 clinical trial of liver‐directed gene therapy (9,10). Interestingly, previous work in our laboratory demonstrated that the adenovirus encoding the gene for the enzyme heme oxygenase‐1 (Ad‐HO‐1) does not elicit the acute inflammation normally caused by adenoviruses, and, in fact, is even able to prevent the acute inflammation caused by a second, simultaneously administered adenovirus (11). The prevention of acute inflammation is necessary for the safe administration of adenoviruses, but this result also invites investigation of Ad‐HO‐1 in models of severe inflammation.…”

Section: Introductionmentioning

confidence: 99%

Remote Liver Injury is Attenuated by Adenovirus‐Mediated Gene Transfer of Heme Oxygenase‐1 During the Systemic Inflammatory Response Syndrome

McCarter¹,

Badhwar²,

Scott³

et al. 2004

Microcirculation

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Cotransfection of heme oxygenase-1 prevents the acute inflammation elicited by a second adenovirus

Cited by 11 publications

References 44 publications

Carbon monoxide‐releasing molecules (CO‐RMs) attenuate the inflammatory response elicited by lipopolysaccharide in RAW264.7 murine macrophages

Carbon monoxide‐releasing molecules (CO‐RMs) attenuate the inflammatory response elicited by lipopolysaccharide in RAW264.7 murine macrophages

Inhibitors of the heme oxygenase – carbon monoxide system: on the doorstep of the clinic?

Remote Liver Injury is Attenuated by Adenovirus‐Mediated Gene Transfer of Heme Oxygenase‐1 During the Systemic Inflammatory Response Syndrome

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