Alveolar inflammation and arachidonate metabolism in monocrotaline-induced pulmonary hypertension

Stenmark, Kurt R.; Morganroth, Melvin L.; Remigio, Linda K.; Voelkel, Norbert F.; Murphy, R.C.; Henson, Peter M.; Mathias, Melvin M.; Reeves, J. T.

doi:10.1152/ajpheart.1985.248.6.h859

Cited by 41 publications

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“…MCTinduced pulmonary endothelial injury is known to be followed by significant pulmonary vascular and alveolar inflammation (34,40), and the latter is thought to be important in subsequent pulmonary vascular remodeling and pulmonary hypertension. Previous studies have shown that inhibition of inflammation by interleukin-1 receptor antagonists (37) or by an antibody that neutralizes monocyte chemotactic and activating factor/monocyte chemoattractant protein-1 (19) alleviate MCT-induced pulmonary hypertension.…”

Section: Discussionmentioning

confidence: 99%

“…Targeted disruption of the 5-LO gene (38) or treatment of animals with diethylcarbamazine (24), MK-886 (an inhibitor of FLAP) (38), or leukotriene antagonists (1,16,23,31) reduced hypoxia-induced pulmonary hypertension. Diethylcarbamazine, an antiparasitic drug that also inhibits 5-LO, was shown to ameliorate the development of pulmonary hypertension caused by monocrotaline (MCT) in rats (34).…”

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confidence: 99%

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Effect of 5-lipoxygenase on the development of pulmonary hypertension in rats

Jones¹,

Walker²,

Song³

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

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. Effect of 5-lipoxygenase on the development of pulmonary hypertension in rats. Am J Physiol Heart Circ Physiol 286: H1775-H1784, 2004. First published January 15, 2004 10.1152/ ajpheart.00281.2003 and its downstream leukotriene products have been implicated in the development of pulmonary hypertension. In this study, we examined the effects of 5-LO overexpression in rat lungs on pulmonary hypertension using a recombinant adenovirus expressing 5-LO (Ad5-LO). Transthoracic echocardiography and right heart catheterization data showed that 5-LO overexpression in the lung did not cause pulmonary hypertension in normal rats; however, it markedly accelerated the progression of pulmonary hypertension in rats treated with monocrotaline (MCT). An increase in pulmonary artery pressure occurred earlier in the rats treated with MCT ϩ Ad5-LO (7-10 days) compared with those treated with control vector, MCT ϩ adenovirus expressing green fluorescent protein (AdGFP), or MCT alone (15-18 days). The weight ratio of the right ventricle to left ventricle plus septum was higher in the MCT ϩ Ad5-LO group than that of the MCT ϩ AdGFP or MCT group (0.45 Ϯ 0.08 vs. 0.35 Ϯ 0.03 or 0.33 Ϯ 0.06). Lung tissue histological sections from MCT ϩ Ad5-LO rats exhibited more severe inflammatory cell infiltration and pulmonary vascular muscularization than those from MCT ϩ AdGFP-or MCT-treated rats. Administration of 5-LO inhibitors, zileuton or MK-886, to either MCT-or MCT ϩ Ad5-LO-treated rats prevented the development of pulmonary hypertension. These data suggest that 5-LO plays a critical role in the progression of pulmonary hypertension in rats and that the detrimental effect of 5-LO is manifest only in the setting of pulmonary vascular endothelial cell dysfunction.inflammation; monocrotaline 5-LIPOXYGENASE (5-LO) catalyzes two consecutive reactions that convert arachidonic acid to leukotriene A 4 (6, 32). The latter is a crucial precursor for the formation of leukotriene B 4 , a potent chemotactic agent (14), and for the formation of leukotrienes C 4 , D 4 , and E 4 (collectively referred to as cysteinyl leukotrienes) (26), substances that cause an increase in vascular permeability (9, 13) and constriction of bronchi (10, 17) and certain types of blood vessels (4, 5). The substrate for 5-LO is generated by phospholipase A 2 (11) and is presented to 5-LO by 5-LO-activating protein (FLAP) (12).5-LO has also been found to participate in other cellular processes, including cell proliferation (3, 39), tyrosine kinase signaling (21), and F-actin polymerization (21,27,29). In addition, 5-LO was found to bind to transforming growth factor (TGF)-␤ receptor I-associated protein (TRAP-1) (30), although the effect of this association is currently unclear.Increased 5-LO expression has been found in the lung tissue of patients with primary pulmonary hypertension, within infiltrating perivascular alveolar macrophages and in small pulmonary artery endothelial cells (41). Several studies also suggested that 5-LO may play a role in the development of pulmonar...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Effect of 5-lipoxygenase on the development of pulmonary hypertension in rats

Jones¹,

Walker²,

Song³

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

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“…MCT is known to cause pulmonary endothelial injury and pulmonary hyper-tension in humans and rats (39) but has little effect in mice (30). 5-LO and its products, leukotrienes, have been previously found to mediate or facilitate the MCT-induced pulmonary hypertension in rats (37,42). We have previously shown that addition of Ad5LO to MCT challenge in rats significantly exacerbates the pulmonary hypertension caused by MCT (17).…”

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confidence: 91%

Inflammation, endothelial injury, and persistent pulmonary hypertension in heterozygous BMPR2-mutant mice

Song

Coleman²,

Shi³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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. Inflammation, endothelial injury, and persistent pulmonary hypertension in heterozygous BMPR2-mutant mice. Am J Physiol Heart Circ Physiol 295: H677-H690, 2008. First published June 13, 2008 doi:10.1152/ajpheart.91519.2007.-Heterozygous bone morphogenetic protein receptor-II-knockout (BMPR2 ϩ/Ϫ ) mice have a similar genetic trait like that in some idiopathic pulmonary arterial hypertension patients. To examine the effect of pulmonary endothelial injury in BMPR2ϩ/Ϫ mice, we challenged the mice with two injections of monocrotaline combined with intratracheal instillation of replicationdeficient adenovirus expressing 5-lipoxygenase (MCTϩAd5LO). After the challenge (1 wk), BMPR2 ϩ/Ϫ mice exhibited a doubling of right ventricular systolic pressure that was greater than that of wildtype mice and remained elevated for 3 wk before heart failure developed. Muscularization and thickening of small pulmonary arterioles was evident in the BMPR2 ϩ/Ϫ lungs at 2 wk after the challenge and became severe at 3 wk. Marked perivascular infiltration of T cells, B cells, and macrophages was associated with the remodeled vessels. Real-time PCR analysis showed that the expression of six endothelial cell markers in lung tissue was decreased to 20 -40% of original levels at 1 wk after the challenge in both BMPR2ϩ/Ϫ and wild-type mice and largely recovered in wild-type (50 -80%) but not BMPR2 ϩ/Ϫ lungs (30 -50%) at 3 wk after the challenge. Macrophage inflammatory protein-1␣ and fractalkine receptor expression doubled in BMPR2ϩ/Ϫ compared with wild-type lungs. Expression of type I and type II BMP receptors, but not transforming growth factor-␤ receptors, in the challenged BMPR2 ϩ/Ϫ and wild-type lungs showed a similar pattern of expression as that of endothelial markers. Apoptotic responses at 1 wk after MCT and Ad5LO challenge were also significantly greater in the BMPR2 ϩ/Ϫ lungs than the wild-type lungs. These data show that BMPR2 ϩ/Ϫ mice are more sensitive to MCTϩAd5LO-induced pulmonary hypertension than wild-type mice. Greater endothelial injury and an enhanced inflammatory response could be the underlying causes of the sensitivity and may work in concert with BMPR2 heterozygosity to promote the development of persistent pulmonary hypertension.heterozygous bone morphogenetic protein receptor-2 knockout mice HETEROZYGOUS GERMLINE MUTATIONS of bone morphogenetic protein receptor-2 (BMPR2) have been found in patients with idiopathic pulmonary arterial hypertension (IPAH) (10,20,46), a progressive disease characterized by extensive remodeling of the pulmonary arterioles and persistent increase of pulmonary artery pressure of unknown cause. Nearly 70% of familial IPAH and 20% of sporadic IPAH patients have a heterozygous BMPR2 mutation (1), but the chance of developing pulmonary arterial hypertension (PAH) among the BMPR2 mutant family members is only 10 -20% (32). Therefore, additional factors are believed to be required for the development of PAH in the BMPR2 mutant carriers.The BMPR2 gene encodes BMPR-II, which forms a complex with ...

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“…Early pathological changes include pulmonary artery endothelial swelling and blebbing (11) and alveolar inflammatory infiltrates (15,16). The subendothelial space appears widened (17)(18)(19), associated with a slight increase in the number of small breaks in the inner elastic lamina compared with normal pulmonary arteries (17).…”

Section: Introductionmentioning

confidence: 99%

The role of vascular injury and hemodynamics in rat pulmonary artery remodeling.

Tanaka

Schuster²,

Davis³

et al. 1996

J. Clin. Invest.

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Vascular remodeling in adult human elastic pulmonary arteries is characterized by diffuse neointimal lesions containing smooth muscle cells expressing extracellular matrix genes. Recent studies suggest vascular injury is needed to initiate remodeling and that growth factor mediators participate in the repair response. However, because neointimal formation is only observed in patients with pulmonary artery blood pressures approaching systemic levels, it has been hypothesized that systemic-like hemodynamic conditions are also necessary. To test that hypothesis, subclavian-pulmonary artery anastomoses were created in Sprague-Dawley rats under three different experimental conditions: no accompanying injury, or after monocrotaline or balloon endarterectomy injury.Pulmonary vascular remodeling was not induced by the subclavian-pulmonary artery anastomosis alone. A nonneointimal pattern of remodeling after mild monocrotalineinduced injury was converted into a neointimal pattern in the presence of the anastomosis. Neointima was also observed after severe, balloon endarterectomy-induced injury even in the absence of anastomosis. Tropoelastin, type I procollagen and TGF-␤ gene expression, and angiotensin converting enzyme immunoreactivity, was confined to the neointima resembling the pattern of gene expression and immunoreactivity in human hypertensive elastic pulmonary artery neointimal lesions. These observations introduce the concepts that the type of injury and the associated hemodynamic conditions can modify the elastic pulmonary artery response to injury.

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Alveolar inflammation and arachidonate metabolism in monocrotaline-induced pulmonary hypertension

Cited by 41 publications

References 0 publications

Effect of 5-lipoxygenase on the development of pulmonary hypertension in rats

Effect of 5-lipoxygenase on the development of pulmonary hypertension in rats

Inflammation, endothelial injury, and persistent pulmonary hypertension in heterozygous BMPR2-mutant mice

The role of vascular injury and hemodynamics in rat pulmonary artery remodeling.

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