N-acetylcysteine inhibits hypoxic pulmonary hypertension most effectively in the initial phase of chronic hypoxia

Lachmanová, Věra; Hnilickova, Olga; Povýsilová, V; Hampl, Václav; Herget, J

doi:10.1016/j.lfs.2004.11.027

Cited by 51 publications

(29 citation statements)

References 16 publications

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“…However, the exact contribution of either ROS sources to PH development remains to be elucidated. The importance of prooxidative metabolism in PH is supported by studies where suppression of oxidative metabolism, including the use of tempol, leads to the reduction of PH development (24)(25)(26)(43)(44)(45).…”

Section: Discussionmentioning

confidence: 99%

Constitutive Reprogramming of Fibroblast Mitochondrial Metabolism in Pulmonary Hypertension

Plecitá–Hlavatá

Tauber

et al. 2016

Am J Respir Cell Mol Biol

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Remodeling of the distal pulmonary artery wall is a characteristic feature of pulmonary hypertension (PH). In hypoxic PH, the most substantial pathologic changes occur in the adventitia. Here, there is marked fibroblast proliferation and profound macrophage accumulation. These PH fibroblasts (PH-Fibs) maintain a hyperproliferative, apoptotic-resistant, and proinflammatory phenotype in ex vivo culture. Considering that a similar phenotype is observed in cancer cells, where it has been associated, at least in part, with specific alterations in mitochondrial metabolism, we sought to define the state of mitochondrial metabolism in PH-Fibs. In PH-Fibs, pyruvate dehydrogenase was markedly inhibited, resulting in metabolism of pyruvate to lactate, thus consistent with a Warburg-like phenotype. In addition, mitochondrial bioenergetics were suppressed and mitochondrial fragmentation was increased in PH-Fibs. Most importantly, complex I activity was substantially decreased, which was associated with down-regulation of the accessory subunit nicotinamide adenine dinucleotide reduced dehydrogenase (ubiquinone) Fe-S protein 4 (NDUFS4). Owing to less-efficient ATP synthesis, mitochondria were hyperpolarized and mitochondrial superoxide production was increased. This pro-oxidative status was further augmented by simultaneous induction of cytosolic nicotinamide adenine dinucleotide phosphate reduced oxidase 4. Although acute and chronic exposure to hypoxia of adventitial fibroblasts from healthy control vessels induced increased glycolysis, it did not induce complex I deficiency as observed in PH-Fibs. This suggests that hypoxia alone is insufficient to induce NDUFS4 down-regulation and constitutive abnormalities in complex I. In conclusion, our study provides evidence that, in the pathogenesis of vascular remodeling in PH, alterations in fibroblast mitochondrial metabolism drive distinct changes in cellular behavior, which potentially occur independently of hypoxia.

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Section: Discussionmentioning

confidence: 99%

Constitutive Reprogramming of Fibroblast Mitochondrial Metabolism in Pulmonary Hypertension

Plecitá–Hlavatá

Tauber

et al. 2016

Am J Respir Cell Mol Biol

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“…For example, indexes of pulmonary hypertension, determined at the end of a prolonged hypoxia, are reduced in rats that were treated with antioxidants at the beginning of the exposure (28,35). By analogy, the present study was designed to test the hypothesis that elevated lung NO production in the first few days of chronic hypoxia contributes to the development of pulmonary hypertension, presumably by contributing to oxidative vascular wall injury.…”

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confidence: 99%

“…23). On the other hand, due to its radical nature, NO may contribute to the oxidative injury to the walls of the pulmonary vessels that appears to initiate their morphological remodeling (27,28,35). Such a hypertension-promoting effect may more or less negate the tone-and proliferation-reducing effects.…”

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confidence: 99%

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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“…Our previous experiments showed that the first week of hypoxic exposure is crucial for the development of HPH (2,6,10). It seems that the discrepancies in the course of recovery are mainly due to differences in the duration and type of hypoxia (continual or intermittent, normobaric or hypobaric) resulting in the various degree of tissue radical injury and different PAP values at the end of exposure.…”

Section: Discussionmentioning

confidence: 99%

Recovery from Hypoxic Pulmonary Hypertension in Rats

Maxová

Baňasová

Povýsilová

et al. 2011

Acta Med. (Hradec Kralove, Czech Repub.)

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Summary:To characterize the time frame of changes in pulmonary arterial pressure, right ventricular hypertrophy and morphology of small pulmonary arteries male Wistar rats were exposed to isobaric hypoxia (3 weeks, F I O 2 0.1) and then let to recover on air for 1 or 5 weeks. Normoxic animals (group N) served as controls. Mean pulmonary arterial pressure (PAP), ratio of the weight of the right heart ventricle to the sum of the weights of the left ventricle and septum (RV/LV+S) and percentage of double laminated pulmonary vessels ( % DL) were measured at the end of hypoxic exposure (group H), after 1 or 5 weeks of recovery (groups 1R and 5R), and in controls kept in air (group N). Three weeks in hypoxia resulted in increase in PAP, RV/LV+S and % DL. After 1 week of recovery RV/LV+S normalized, PAP decreased, while % DL did not change. After 5 weeks in air PAP returned to control values and % DL diminished significantly but did not normalize. Our results suggest that recovery depends on the degree of HPH and that knowledge of the time-frame of recovery is important for future studies in our rat model.

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N-acetylcysteine inhibits hypoxic pulmonary hypertension most effectively in the initial phase of chronic hypoxia

Cited by 51 publications

References 16 publications

Constitutive Reprogramming of Fibroblast Mitochondrial Metabolism in Pulmonary Hypertension

Constitutive Reprogramming of Fibroblast Mitochondrial Metabolism in Pulmonary Hypertension

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

Recovery from Hypoxic Pulmonary Hypertension in Rats

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