Free radical biology and medicine: it's a gas, man!

Pryor, William A.; Houk, K. N.; Foote, Christopher S.; Fukuto, Jon M.; Ignarro, Louis J.; Squadrito, G; Davies, Kelvin J.A.

doi:10.1152/ajpregu.00614.2005

Cited by 421 publications

(361 citation statements)

References 246 publications

(263 reference statements)

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“…The reactive oxygen molecule hydrogen peroxide (H 2 O 2 ), the end product of enzymatic conversion of O 2 -by superoxide dismutase (SOD), is also important in the regulation of HIF1 (REFS 28,30). Nitric oxide (NO), also a free radical, is a multifunctional biological gas that is an important cell signalling molecule at low concentrations but can be cytotoxic at high concentrations 31,32 . There are three isoforms of nitric oxide synthase that produce NO from l-arginine 33 .…”

Section: Regulation Of Hif1 By Free Radicalsmentioning

confidence: 99%

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

2008

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Hypoxia and free radicals, such as reactive oxygen and nitrogen species, can alter the function and/or activity of the transcription factor hypoxia-inducible factor 1 (HIF1). Interplay between free radicals, hypoxia and HIF1 activity is complex and can influence the earliest stages of tumour development. The hypoxic environment of tumours is heterogeneous, both spatially and temporally, and can change in response to cytotoxic therapy. Free radicals created by hypoxia, hypoxia-reoxygenation cycling and immune cell infiltration after cytotoxic therapy strongly influence HIF1 activity. HIF1 can then promote endothelial and tumour cell survival. As discussed here, a constant theme emerges: inhibition of HIF1 activity will have therapeutic benefit.Virchow first described the abnormal structure of tumour vessels using contrast agents in human tumours as early as the mid 1800s 1 . A few decades later, Goldman was among the first to suggest that angiogenesis was associated with tumour growth 2 . A number of other investigators in the nineteenth and early twentieth centuries evaluated tumour angiogenesis, using techniques such as microangiography, vascular casting and window chamber models. Warren has reviewed this early work in great detail 3 . Folkman illuminated the crucial role of tumour angiogenesis by hypothesizing that tumour growth was dependent upon angiogenesis and that, if angiogenesis could be inhibited, it could maintain tumour deposits in a quiescent state 4 . These early works set the stage for the concept that tumours require angiogenesis to provide a nutrient supply. Although it is well-established that angiogenesis occurs in nearly all human solid tumours, it does not occur in an efficient manner, leading to spatial and temporal inadequacies in delivery of oxygen and other nutrients. These inefficiencies in nutrient delivery lead to a brutal cycle of unsatisfied demand by the tumour, which drives continued aberrant angiogenesis.The transcription factor hypoxia-inducible factor 1 (HIF1) plays an important part in tumour progression by upregulating genes that control angiogenesis, meta-stasis and resistance to oxidative stress. It also controls the switch to anaerobic metabolism, which can maintain cell NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript viability under hypoxic conditions. Further, HIF1 activity can promote treatment resistance by promoting endothelial and tumour cell survival after cytotoxic therapy. The mechanisms that control HIF1 activity are complex and are influenced by microenvironmental factors involving hypoxia, oxidative and nitrosative stress.In this Review we will discuss four important and interrelated aspects of tumour hypoxia. First, we will define the hypoxic response, discussing its relevance in influencing tumour cell survival, behaviour and angiogenesis. We will examine the physiological factors that contribute to hypoxia, emphasizing a perspective based on spatial and temporal dysfunction of tumour microcirculation. The question of whethe...

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Section: Regulation Of Hif1 By Free Radicalsmentioning

confidence: 99%

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

2008

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“…A great deal of scientific focus over the last two decades has been aimed at elucidating the role of nitric oxide (NO) and carbon monoxide in physiology and pathophysiology (3). The critical function of nitric oxide was made apparent by the finding that it was central in smooth muscle relaxation and vasodilation (7,8) and necessary for the maintenance of vascular homeostasis (9).…”

mentioning

confidence: 99%

Hydrogen sulfide attenuates myocardial ischemia-reperfusion injury by preservation of mitochondrial function

Elrod¹,

Calvert²,

Morrison

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

1,041

892

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The recent discovery that hydrogen sulfide (H2S) is an endogenously produced gaseous second messenger capable of modulating many physiological processes, much like nitric oxide, prompted us to investigate the potential of H2S as a cardioprotective agent. In the current study, we demonstrate that the delivery of H2S at the time of reperfusion limits infarct size and preserves left ventricular (LV) function in an in vivo model of myocardial ischemiareperfusion (MI-R). This observed cytoprotection is associated with an inhibition of myocardial inflammation and a preservation of both mitochondrial structure and function after I-R injury. Additionally, we show that modulation of endogenously produced H2S by cardiac-specific overexpression of cystathionine ␥-lyase (␣-MHC-CGL-Tg mouse) significantly limits the extent of injury. These findings demonstrate that H2S may be of value in cytoprotection during the evolution of myocardial infarction and that either administration of H2S or the modulation of endogenous production may be of clinical benefit in ischemic disorders.

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“…At the same time as the permeability of P M,CO 2 ϭ 3.2 cm/s allows CO 2 to pass membranes freely (22), the NH 3 permeability P M,NH 3 ϭ 0.016 cm/s (24) indicates that a cholesterol-containing epithelial membrane acts as a barrier and, consequently, that membrane channels (aquaporin-8) facilitate NH 3 diffusion (18). The different findings for NH 3 and CO 2 are in agreement with Overton's rule (25,26) which, based on the biphasic partition coefficients (Table 1) predicts the large difference in P M .…”

mentioning

confidence: 99%

“…H 2 S is engaged in regulation and modulation of physiological functions such as vasorelaxation, vasodilatation, blood pressure modulation, and inhibition of apoptosis in a number of cell types (2)(3)(4)(5). It is an important mediator of endotoxic shock (6) and acute inflammation, acting at the leukocyte-endothelium interface (7).…”

mentioning

confidence: 99%

No facilitator required for membrane transport of hydrogen sulfide

Mathai

Missner²,

Kügler

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

330

226

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Hydrogen sulfide (H2S) has emerged as a new and important member in the group of gaseous signaling molecules. However, the molecular transport mechanism has not yet been identified. Because of structural similarities with H 2O, it was hypothesized that aquaporins may facilitate H 2S transport across cell membranes. We tested this hypothesis by reconstituting the archeal aquaporin AfAQP from sulfide reducing bacteria Archaeoglobus fulgidus into planar membranes and by monitoring the resulting facilitation of osmotic water flow and H2S flux. To measure H2O and H2S fluxes, respectively, sodium ion dilution and buffer acidification by proton release (H 2S % H ؉ ؉ HS ؊ ) were recorded in the immediate membrane vicinity. Both sodium ion concentration and pH were measured by scanning ion-selective microelectrodes. A lower limit of lipid bilayer permeability to H 2S, P M,H 2 S > 0.5 ؎ 0.4 cm/s was calculated by numerically solving the complete system of differential reaction diffusion equations and fitting the theoretical pH distribution to experimental pH profiles. Even though reconstitution of AfAQP significantly increased water permeability through planar lipid bilayers, PM,H 2 S remained unchanged. These results indicate that lipid membranes may well act as a barrier to water transport although they do not oppose a significant resistance to H 2S diffusion. The fact that cholesterol and sphingomyelin reconstitution did not turn these membranes into an H2S barrier indicates that H 2S transport through epithelial barriers, endothelial barriers, and membrane rafts also occurs by simple diffusion and does not require facilitation by membrane channels. aquaporins ͉ gas transport ͉ membrane permeability ͉ unstirred layer ͉ signaling

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Free radical biology and medicine: it's a gas, man!

Cited by 421 publications

References 246 publications

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

Hydrogen sulfide attenuates myocardial ischemia-reperfusion injury by preservation of mitochondrial function

No facilitator required for membrane transport of hydrogen sulfide

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