Enhanced expression of inducible nitric oxide synthase without vasodilator effect in chronically infected lungs

Cadogan, Elaine; Hopkins, Natalie; Giles, Shay; Bannigan, John; Moynihan, John B; McLoughlin, Paul

doi:10.1152/ajplung.1999.277.3.l616

Cited by 23 publications

(37 citation statements)

References 27 publications

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“…For instance, in chronically-infected rat lungs pulmonary hypertension did not occur and right ventricular hypertrophy was not observed despite the appearance of thickened pulmonary vessel walls. 6,7 Similar observations have been made in humans with chronic-obstructive pulmonary disease where marked thickening of the walls of the pulmonary arteries have been observed in the absence of pulmonary hypertension. 8 One possible explanation for these findings is that thickening occurred in an outward direction such that it did not reduce the vascular lumen.…”

supporting

confidence: 67%

Vascular Remodeling Versus Vasoconstriction in Chronic Hypoxic Pulmonary Hypertension

Stenmark

McMurtry

2005

Circulation Research

118

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C hronic or sustained pulmonary hypertension is a complication of residence at high altitudes and chronic lung diseases such as chronic obstructive pulmonary disease, cystic fibrosis, bronchiectasis, asthma, and sleep apnea. Alveolar hypoxia is an important (though probably not exclusive) contributor to the pulmonary hypertension observed in these conditions. Further, it is widely accepted that secondary hypoxic pulmonary hypertension is strongly associated with increased morbidity and reduced survival. 1,2 These facts have led to intense research efforts to identify the underlying mechanisms contributing to this condition, with the ultimate goal of identifying and developing novel therapeutic interventions. This work has relied heavily on the use of animal models, and one of the most commonly used is exposure of rats to chronic-hypoxic conditions by nitrogen dilution or hypobaria. Observations, predominately in this model, have led to the longstanding and widely accepted theory that chronic hypoxic pulmonary hypertension results from a combination of sustained vasoconstriction and vascular remodeling. It is generally believed that the contribution of vasoconstriction is greatest early in the disease process and that structural remodeling of the pulmonary vascular bed becomes progressively more important over time. That structural change is an important determinant of increased resistance and pressure in chronic pulmonary hypertension is supported by observations that over time of exposure to hypoxia, acute reexposure to normal or even high levels of inspired oxygen becomes progressively less effective in reducing the pulmonary arterial pressure. This lack of responsiveness to oxygen, or even to other pulmonary vasodilators such as Ca 2ϩ channel blockers, has led to the concept that chronic hypoxic pulmonary hypertension is associated with a "fixed" structural component responsible for the increased pulmonary vascular resistance. The structural changes thought to contribute to the increased vascular resistance have been broadly characterized into 2 processes: (1) inward remodeling of the pulmonary artery wall and (2) a reduction in the total number of small peripheral pulmonary arteries (a process referred to as rarefaction or pruning of the pulmonary vasculature).The work presented by Hyvel et al challenges, at least in certain ways, both of these concepts. 3 Pulmonary vascular remodeling refers to a process that causes thickening of the arterial wall and is thought to increase resistance by physical encroachment of the lumen of small peripheral pulmonary arteries and arterioles. Because intimal thickening is not usually observed in hypoxic pulmonary hypertension, this reduction in luminal area is believed to be attributable largely to constrictive medial and adventitial thickening. However, using different lung preparation techniques than have been used in most other hypoxic studies (ie, the pulmonary vasculature was "maximally" vasodilated by perfusion with calcium-free plus EGTA physiological saline solution...

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confidence: 67%

Vascular Remodeling Versus Vasoconstriction in Chronic Hypoxic Pulmonary Hypertension

Stenmark

McMurtry

2005

Circulation Research

118

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“…Enhanced iNOS expression not accompanied by NO overproduction has been occasionally reported (9,13,37). Thus to support our hypothesis of a causative role of elevated NO in the initiation of hypoxic pulmonary hypertension, it was necessary not only to show early iNOS induction in lung vessels (Figs.…”

Section: Bw CI Rv and Lvϩs Wet Weight And Their Ratio (Rv/lvϩs) In mentioning

confidence: 85%

Pulmonary vascular iNOS induction participates in the onset of chronic hypoxic pulmonary hypertension

Hampl

Bíbová²,

Baňasová³

et al. 2006

American Journal of Physiology-Lung Cellular and Molecular Phys

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Pathogenesis of hypoxic pulmonary hypertension is initiated by oxidative injury to the pulmonary vascular wall. Because nitric oxide (NO) can contribute to oxidative stress and because the inducible isoform of NO synthase (iNOS) is often upregulated in association with tissue injury, we hypothesized that iNOS-derived NO participates in the pulmonary vascular wall injury at the onset of hypoxic pulmonary hypertension. An effective and selective dose of an iNOS inhibitor, L-N 6 -(1-iminoethyl)lysine (L-NIL), for chronic peroral treatment was first determined (8 mg/l in drinking water) by measuring exhaled NO concentration and systemic arterial pressure after LPS injection under ketamineϩxylazine anesthesia. A separate batch of rats was then exposed to hypoxia (10% O2) and given L-NIL or a nonselective inhibitor of all NO synthases, N G -nitro-L-arginine methyl ester (L-NAME, 500 mg/l), in drinking water. Both inhibitors, applied just before and during 1-wk hypoxia, equally reduced pulmonary arterial pressure (PAP) measured under ketamineϩxylazine anesthesia. If hypoxia continued for 2 more wk after L-NIL treatment was discontinued, PAP was still lower than in untreated hypoxic controls. Immunostaining of lung vessels showed negligible iNOS presence in control rats, striking iNOS expression after 4 days of hypoxia, and return of iNOS immunostaining toward normally low levels after 20 days of hypoxia. Lung NO production, measured as NO concentration in exhaled air, was markedly elevated as early as on the first day of hypoxia. We conclude that transient iNOS induction in the pulmonary vascular wall at the beginning of chronic hypoxia participates in the pathogenesis of pulmonary hypertension. pulmonary circulation; nitric oxide; rat; inducible nitric oxide synthase SINCE THE DISCOVERY THAT NITRIC OXIDE (NO) is formed in mammalian cells as an endogenous mediator, many attempts were made to define its possible role in the pathogenesis of pulmonary hypertension (reviewed in Ref. 23). Although the capacity of lung vessels to produce NO can be reduced in terminal phases of severe pulmonary hypertension (15), possibly due to the progressive endothelial damage, less advanced stages (at least in adults) are associated with increased expression of NO synthase (NOS) and augmented NO production (reviewed in Ref. 23). This is particularly well documented in the frequently used and clinically relevant model of pulmonary hypertension elicited by chronic hypoxia.In principle, as the actions of NO in the body are multifaceted, two main functional consequences of the elevated lung NO synthesis in chronic hypoxic pulmonary hypertension are possible. On one hand, the vasodilator and antiproliferative effects of NO may limit the extent of pulmonary vascular resistance elevation. This possibility is supported by numerous reports that acute administration of NOS blockers, such as N G -nitro-L-arginine methyl ester (L-NAME), increases perfusion pressure in lungs isolated from chronically hypoxic animals more than in normoxic controls (rev...

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“…Another important mechanism of lung damage in infection-induced lung injury is increased inducible nitric oxide synthase expression, increased nitric oxide production, and the formation of reactive nitrogen intermediates leading to oxidative tissue damage (40). However, buffered hypercapnia did not increase nitrosothiol, an important end product of reactive nitrogen species-mediated injury, in the endotoxin-treated or E. coliinfected lungs.…”

Section: Buffered Hypercapnia and Lung Injurymentioning

confidence: 90%

Infection-induced lung injury is worsened after renal buffering of hypercapnic acidosis

Nichol

O'Cronin

Howell

et al. 2009

Critical Care Medicine

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Our results demonstrate that infection-induced injury in vivo is worsened after renal buffering of hypercapnic acidosis independently of any changes in tidal volume. These findings have important implications for our understanding of the pathogenesis of infection-induced lung injury during the use protective ventilation strategies that permits buffered hypercapnia and during infective exacerbations of chronic lung diseases associated with sustained hypercapnia.

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Enhanced expression of inducible nitric oxide synthase without vasodilator effect in chronically infected lungs

Cited by 23 publications

References 27 publications

Vascular Remodeling Versus Vasoconstriction in Chronic Hypoxic Pulmonary Hypertension

Vascular Remodeling Versus Vasoconstriction in Chronic Hypoxic Pulmonary Hypertension

Pulmonary vascular iNOS induction participates in the onset of chronic hypoxic pulmonary hypertension

Infection-induced lung injury is worsened after renal buffering of hypercapnic acidosis

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