Mechanistic imbalance of pulmonary vasomotor control in progressive lung injury

Fullerton, David A.; Hahn, Angela R.; McIntyre, Robert C.

doi:10.1016/s0039-6060(96)80220-0

Cited by 18 publications

(11 citation statements)

References 17 publications

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“…The different results could be related to the vascular preparation (pulmonary artery versus isolated perfused lung), or the NO-cGMP blocker used (L-NAME and ODQ versus hydroquinone and methylene blue). The reduced ACh-and SNP-induced relaxation in pulmonary arteries of MCT-treated rats is consistent with the report that both endothelium-dependent and -independent relaxation are reduced in the rat model of MCT-induced progressive lung injury (Fullerton et al, 1996).…”

Section: Discussionsupporting

confidence: 91%

“…Large vessels such as the aorta, skeletal muscle, and diaphragmatic and mesenteric arterioles could be affected (Doyle and Walker, 1991;Kuwahira et al, 1993;Toporsian and Ward, 1997;Auer and Ward, 1998). Although MCT treatment may cause both pulmonary and systemic vascular inflammation and endothelial damage, MCT-treated rats have been used as a model of progressive lung injury and PH (Gillespie et al, 1986;Fullerton et al, 1996). In our hypoxia and MCT models of PH, we found no changes in the responsiveness of the mesenteric vessels jpet.aspetjournals.org to vasoconstrictor or vasodilator stimuli, indicating specific changes in the pulmonary but not the systemic circulation in experimental PH.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have examined pulmonary vascular function in animal models of PH with variable results (Adnot et al, 1991;Fullerton et al, 1996;Gillespie et al, 1986;Shimoda et al, 2000;Barman, 2007). The variable results could be due to differences in the pulmonary hypertensive animal model, the experimental preparation (isolated perfused lung versus vascular rings), or the vasoactive mediators used.…”

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confidence: 99%

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Impaired Vasoconstriction and Nitric Oxide-Mediated Relaxation in Pulmonary Arteries of Hypoxia- and Monocrotaline-Induced Pulmonary Hypertensive Rats

Mam

Tanbe²,

Vitali³

et al. 2009

J Pharmacol Exp Ther

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Pulmonary hypertension (PH) is a life-threatening disease with unclear vascular mechanisms. We tested whether PH involves abnormal pulmonary vasoconstriction and impaired vasodilation. Male Sprague-Dawley rats were exposed to hypoxia (9% O 2 ) for 2 weeks or injected with single dose of monocrotaline (MCT, 60 mg/kg s.c.). Control rats were normoxic or injected with saline. After the hemodynamic measurements were performed, pulmonary and mesenteric arteries were isolated for measurement of vascular function. Hematocrit was elevated in hypoxic rats. Right ventricular systolic pressure and Fulton's Index [right/(left ϩ septum) ventricular weight] were greater in hypoxic and MCT-treated rats than in normoxic rats. Pulmonary artery contraction by phenylephrine and 96 mM KCl was less in hypoxic and MCT-treated rats than in normoxic rats. Acetylcholine-induced relaxation was less in the pulmonary arteries of hypoxic and MCT-treated rats than of normoxic rats, suggesting reduced effects of endothelium-derived vasodilators. The nitric oxide synthase inhibitor, N -nitro-L-arginine methyl ester, and the guanylate cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, inhibited acetylcholine relaxation, suggesting that it was mediated by nitric oxide (NO)-cGMP. The NO donor sodium nitroprusside caused less relaxation in the pulmonary arteries of hypoxic and MCT-treated than of normoxic rats, suggesting decreased responsiveness of vascular smooth muscle cells (VSMCs) to vasodilators. Phenylephrine and KCl contraction and acetylcholine and sodium nitroprusside relaxation were not different in the mesenteric arteries from all groups. In lung tissue sections, the wall thickness of pulmonary arterioles was greater in hypoxic and MCT-treated rats than in normoxic rats. The specific reductions in pulmonary, but not systemic, arterial vasoconstriction and vasodilation in hypoxiaand MCT-induced PH are consistent with the possibility of de-differentiation of pulmonary VSMCs to a more proliferative/ synthetic and less contractile phenotype in PH.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Impaired Vasoconstriction and Nitric Oxide-Mediated Relaxation in Pulmonary Arteries of Hypoxia- and Monocrotaline-Induced Pulmonary Hypertensive Rats

Mam

Tanbe²,

Vitali³

et al. 2009

J Pharmacol Exp Ther

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“…A plausible explanation for the reduced ACh relaxation in hypoxic and MCT-treated rats is possible structural changes in the pulmonary vascular wall and decreased responsiveness of pulmonary VSMCs to vasodilators. This is supported by the reduced pulmonary artery relaxation to the NO donor SNP in hypoxic and MCT-treated rats, and consistent with the report that both endothelium-dependent and -independent relaxation are reduced in the rat model of MCT-induced progressive lung injury (25). Consequently, the enhanced SNP-induced relaxation in pulmonary arteries of hypoxic and MCT rats treated with NH 4 Cl can be explained by prevention or reversal of structural changes in the pulmonary vasculature and improved responsiveness of pulmonary VSMCs to vasodilators.…”

Section: Discussionsupporting

confidence: 91%

“…We and others have shown that PH in hypoxic and MCT-treated rats is associated with reduced pulmonary responsiveness to vasoconstrictors and endogenous and exogenous nitrovasodilators (2,25,27,50,67) and extensive pulmonary arteriolar thickening and remodeling (9,12,44,50,53,59). Multiple mechanisms may contribute to pulmonary vascular remodeling in PH including resident medial pulmonary VSMC hypertrophy and hyperplasia and a phenotypic switch from a contractile to a synthetic phenotype; transdifferentiation of circulating and resident progenitor, adventitial, or endothelial cells to a VSMC-like phenotype; and intimal and adventitial changes.…”

Section: Discussionmentioning

confidence: 99%

Improved pulmonary vascular reactivity and decreased hypertrophic remodeling during nonhypercapnic acidosis in experimental pulmonary hypertension

Christou

Reslan

Mam

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

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Christou H, Reslan OM, Mam V, Tanbe AF, Vitali SH, Touma M, Arons E, Mitsialis SA, Kourembanas S, Khalil RA. Improved pulmonary vascular reactivity and decreased hypertrophic remodeling during nonhypercapnic acidosis in experimental pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 302: L875-L890, 2012. First published January 27, 2012; doi:10.1152/ajplung.00293.2011.-Pulmonary hypertension (PH) is characterized by pulmonary arteriolar remodeling with excessive pulmonary vascular smooth muscle cell (VSMC) proliferation. This results in decreased responsiveness of pulmonary circulation to vasodilator therapies. We have shown that extracellular acidosis inhibits VSMC proliferation and migration in vitro. Here we tested whether induction of nonhypercapnic acidosis in vivo ameliorates PH and the underlying pulmonary vascular remodeling and dysfunction. Adult male Sprague-Dawley rats were exposed to hypoxia (8.5% O2) for 2 wk, or injected subcutaneously with monocrotaline (MCT, 60 mg/kg) to develop PH. Acidosis was induced with NH4Cl (1.5%) in the drinking water 5 days prior to and during the 2 wk of hypoxic exposure (prevention protocol), or after MCT injection from day 21 to 28 (reversal protocol). Right ventricular systolic pressure (RVSP) and Fulton's index were measured, and pulmonary arteriolar remodeling was analyzed. Pulmonary and mesenteric artery contraction to phenylephrine (Phe) and high KCl, and relaxation to acetylcholine (ACh) and sodium nitroprusside (SNP) were examined ex vivo. Hypoxic and MCT-treated rats demonstrated increased RVSP, Fulton's index, and pulmonary arteriolar thickening. In pulmonary arteries of hypoxic and MCT rats there was reduced contraction to Phe and KCl and reduced vasodilation to ACh and SNP. Acidosis prevented hypoxia-induced PH, reversed MCT-induced PH, and resulted in reduction in all indexes of PH including RVSP, Fulton's index, and pulmonary arteriolar remodeling. Pulmonary artery contraction to Phe and KCl was preserved or improved, and relaxation to ACh and SNP was enhanced in NH4Cl-treated PH animals. Acidosis alone did not affect the hemodynamics or pulmonary vascular function. Phe and KCl contraction and ACh and SNP relaxation were not different in mesenteric arteries of all groups. Thus nonhypercapnic acidosis ameliorates experimental PH, attenuates pulmonary arteriolar thickening, and enhances pulmonary vascular responsiveness to vasoconstrictor and vasodilator stimuli. Together with our finding that acidosis decreases VSMC proliferation, the results are consistent with the possibility that nonhypercapnic acidosis promotes differentiation of pulmonary VSMCs to a more contractile phenotype, which may enhance the effectiveness of vasodilator therapies in PH. pulmonary artery; pulmonary circulation; nitric oxide; vascular smooth muscle PULMONARY HYPERTENSION (PH) is a serious disease and a major and expanding public health problem with ϳ1,000 new patients diagnosed every year in the United States (6,20). PH is characterized by increased pulmonary arterial pre...

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Postnatal management and long‐term outcome for survivors with congenital diaphragmatic hernia

Chiu¹,

Hedrick²

2008

Prenatal Diagnosis

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Significant advances in the postnatal management of patients with congenital diaphragmatic hernia (CDH) have resulted in a remarkable improvement in survival rates over the past two decades. The success of current postnatal management of CDH patients has rendered fetal intervention to be limited to the most severe cases, and the role for prenatal treatment of CDH patients remains unclear. The adoption of lung-preserving strategies including high-frequency oscillatory ventilation (HFOV) and extracorporeal membrane oxygenation (ECMO) have improved CDH outcomes especially in those patients with significant ventilatory or circulatory compromise. Survival rates of up to 90% are being reported in some high-volume centers. However, the increased survival in CDH patients has been accompanied by an increase in neurological, nutritional and musculoskeletal morbidity among the long-term survivors. This has resulted in the need to provide resources for the long-term follow-up and support of this patient population. In this article, the postnatal management strategies and primary and secondary outcomes of high-volume international pediatric surgical centers will be reviewed. Finally, the role of a multidisciplinary management team for the follow-up of long-term CDH survivors will be discussed.

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Mechanistic imbalance of pulmonary vasomotor control in progressive lung injury

Cited by 18 publications

References 17 publications

Impaired Vasoconstriction and Nitric Oxide-Mediated Relaxation in Pulmonary Arteries of Hypoxia- and Monocrotaline-Induced Pulmonary Hypertensive Rats

Impaired Vasoconstriction and Nitric Oxide-Mediated Relaxation in Pulmonary Arteries of Hypoxia- and Monocrotaline-Induced Pulmonary Hypertensive Rats

Improved pulmonary vascular reactivity and decreased hypertrophic remodeling during nonhypercapnic acidosis in experimental pulmonary hypertension

Postnatal management and long‐term outcome for survivors with congenital diaphragmatic hernia

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