PAF receptor blockade inhibits lung vascular changes in the rat monocrotaline model

Ono, Shigehiro; Voelkel, Norbert F.

doi:10.1007/bf00164753

Cited by 13 publications

(5 citation statements)

References 18 publications

(35 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In support of the latter mechanism is the observation in the present report that MCT induced widespread EC apoptosis as well as prior evidence for significant loss of pulmonary microvasculature in MCT-induced PH. 28 However, it is possible that MCT also reduced the Tie-2 expression in the remaining microvascular endothelial cells in a manner similar to hypoxia. 24 The present study directly tested the role of the Tie-2 pathway in the development of experimental PH by overexpressing the Ang-1 gene, targeted to the pulmonary microvasculature.…”

Section: Discussionmentioning

confidence: 99%

Protective Role of Angiopoietin-1 in Experimental Pulmonary Hypertension

Zhao

Campbell

Robb

et al. 2003

Circulation Research

156

109

View full text Add to dashboard Cite

Abstract-Angiopoietin-1 (Ang-1), a newly discovered ligand of the endothelial-specific tyrosine kinase receptor Tie-2, has been found to promote cell survival, vascular maturation, and stabilization. We hypothesized that Ang-1 gene transfer to the pulmonary microcirculation would improve pulmonary hemodynamics and vascular remodeling in experimental pulmonary hypertension. Rat pulmonary artery smooth muscle cells were transfected with Ang-1 cDNA or null (pFLAG-CMV-1) vector. Syngeneic Fisher 344 rats were treated with monocrotaline (MCT) (75 mg/kg IP) with or without delivery of 5ϫ10 5 Ang-1-transfected cells into the right jugular vein. After 28 days, plasmid-derived Ang-1 mRNA was consistently and robustly detected by reverse transcriptase-polymerase chain reaction in lungs from all animals receiving Ang-1 gene therapy. Tie-2 receptor expression was markedly downregulated in rats treated with MCT, and this was partially restored by gene therapy with Ang-1. Animals receiving MCT exhibited 77% mortality by 28 days. In contrast, in pAng-1-treated animals, the 28-day mortality was only 14% (PϽ0.0001). In addition, right ventricular systolic pressure was reduced from 52Ϯ1.3 mm Hg in the MCT-treated group to 38Ϯ1.3 mm Hg by Ang-1 gene transfer (PϽ0.01), whereas the measurement of right to left ventricular plus septal weight ratio was also reduced from 0.41Ϯ0.03 to 0.31Ϯ0.01 (PϽ0.05). Moreover, MCT resulted in increased apoptosis, mainly in the microvasculature, and reduced endothelial NO synthase mRNA expression, both of which were prevented by Ang-1 gene transfer. Thus, cell-based gene transfer with Ang-1 improved survival and pulmonary hemodynamics in experimental pulmonary hypertension by a mechanism involving the inhibition of apoptosis and protection of the pulmonary microvasculature.

show abstract

Section: Discussionmentioning

confidence: 99%

Protective Role of Angiopoietin-1 in Experimental Pulmonary Hypertension

Zhao

Campbell

Robb

et al. 2003

Circulation Research

156

109

View full text Add to dashboard Cite

show abstract

“…MCT led to an increase in lung tissue IL-Ia as measured by RIA and to an increase in lung tissue mRNA for IL-Ia, IL-I.6, and IL-Ira. Although we did not perform quantitative morphometric analysis as in our previous studies (5,7), it is our impression that IL-Ira treatment in the MCT model reduced the degree of inflammation and the degree of collagen formation in the lungs. Since we did not measure IL-I.6 tissue levels and since IL-Ira inhibits the actions of both IL-Ia and IL-I.6, we cannot determine with certainty which of the two cytokine forms contributes to the lung vascular alterations and to the development of pulmonary hypertension in the MCT model.…”

Section: Lung Histologymentioning

confidence: 91%

“…We have recently reported that chronic administration of platelet-activating factor (PAF) receptor antagonists prevents the development of pulmonary hypertension in both models (2,6,7), suggesting that the ether lipid PAF directly or indirectly is involved in the vascular remodeling and pulmonary hypertension in these animal models. Sequestration of granulocytes in pulmonary interstitium and in small lung (Received in original form December 30, 1993 and in revised form June 15, 1994) vessels is a feature of a chronic sheep model where pulmonary hypertension develops with chronic air embolization (11,12).…”

mentioning

confidence: 99%

“…There are two widely used small animal models of chronic pulmonary hypertension: exposure to chronic hypoxia (1, 2) and the "inflammatory" model of pulmonary hypertension in rats injected with the alkaloid monocrotaline (MCT) (3)(4)(5)(6)(7)(8)(9)(10). We have recently reported that chronic administration of platelet-activating factor (PAF) receptor antagonists prevents the development of pulmonary hypertension in both models (2,6,7), suggesting that the ether lipid PAF directly or indirectly is involved in the vascular remodeling and pulmonary hypertension in these animal models.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Interleukin-1 receptor antagonist treatment reduces pulmonary hypertension generated in rats by monocrotaline.

Voelkel

Tuder²,

Bridges³

et al. 1994

Am J Respir Cell Mol Biol

197

146

View full text Add to dashboard Cite

Chronic pulmonary hypertension is associated with significant vascular remodeling. We demonstrated recently in the monocrotaline (MCT) and chronic hypoxia rat models of pulmonary hypertension that treatment with platelet-activating factor (PAF) antagonists inhibited the development of chronic pulmonary hypertension. PAF and other lipid mediators interact with interleukin-1. We postulated that chronic treatment with a recombinant human interleukin-1 receptor antagonist (IL-1ra) would inhibit development of chronic pulmonary hypertension in animal models. Rats were either injected with (60 mg/kg) MCT or exposed to a stimulated high altitude of 16,000 feet; half of the animals were treated with twice-daily injections (2 mg/kg) of IL-1ra. At 3 wk after MCT injection or 3 wk of hypoxic exposure, pulmonary artery pressure and right heart ventricle weight/(left ventricle and septum weight), RV/(LV + S), were measured. IL-1ra treatment reduced pulmonary hypertension and right heart hypertrophy in the MCT model, but not in the chronic hypoxia model. Measurement of lung homogenate IL-1 alpha by radioimmunoassay showed elevated levels in the MCT-treated rats throughout the 3-wk observation period. IL-1ra treatment reduced the levels of IL-1 alpha in lung tissue in most of the MCT-treated rats. MCT treatment was also associated with an increase in lung mRNA for IL-1 alpha, IL-1 beta, and IL-1ra. Immunohistology, using an antibody against rat IL-1 alpha, revealed staining of alveolar structures and of vascular and bronchial smooth muscle. In situ hybridization using a human IL-1 alpha cDNA probe demonstrated increased expression of the IL-1 alpha gene in the lung cells after endotoxin or MCT treatment. Northern blot analysis demonstrated low-level expression of IL-1 alpha mRNA in extracts of normal rat lung and increased expression after endotoxin or MCT treatment. We conclude that chronic treatment with human IL-1ra inhibited the development of pulmonary hypertension in the inflammatory (MCT) model, but not in the chronically hypoxic rats. This result indicates that IL-1 participates in the pathogenesis of some forms of pulmonary hypertension.

show abstract

“…25 It is likely, however, that the direct actions of VEGF, including those on endothelial cell growth and survival, also contributed to the reduction in development of PH after MCT injection. MCT exposure has been shown to result in a significant decrease in the overall number of pulmonary microvessels, 26 which, together with the vasoconstriction and hypertrophic remodeling of the remaining arteries and arterioles, leads to the characteristic decrease in pulmonary vascular conductance observed in this condition. Because the hepatic metabolites of this plant alkaloid 27 have been reported to cause a selective injury to the pulmonary vascular endothelium, 28 it is possible that the mitogenic effects of VEGF accelerated endothelial regrowth and recovery in this model.…”

Section: Vegf In Pulmonary Hypertensionmentioning

confidence: 99%

Cell-Based Gene Transfer of Vascular Endothelial Growth Factor Attenuates Monocrotaline-Induced Pulmonary Hypertension

et al. 2001

View full text Add to dashboard Cite

Background-Pulmonary arterial hypertension is characterized by increased pulmonary vascular resistance secondary to a decrease in the caliber and number of pulmonary vascular channels. We hypothesized that the targeted overexpression of an angiogenic factor within the lung would potentially minimize the development and progression of pulmonary arterial hypertension by preventing the loss of existing vessels or by inducing the development of new blood vessels within the lung. Methods and Results-We used a cell-based method of gene transfer to the pulmonary microvasculature by delivering syngeneic smooth muscle cells overexpressing vascular endothelial growth factor (VEGF)-A to inbred Fisher 344 rats in which pulmonary hypertension was induced with the pulmonary endothelial toxin monocrotaline. Four weeks after simultaneous endothelial injury and cell-based gene transfer, right ventricular (RV) hypertension and RV and vascular hypertrophy were significantly decreased in the VEGF-treated animals. Four weeks after gene transfer, the plasmid VEGF transcript was still detectable in the pulmonary tissue of animals injected with VEGF-transfected cells, demonstrating survival of the transfected cells and persistent transgene expression. In addition, delay of cell-based gene transfer until after the development of pulmonary hypertension also resulted in a significant decrease in the progression of RV hypertension and hypertrophy. Conclusions-These results indicate that cell-based VEGF gene transfer is an effective method of preventing the development and progression of pulmonary hypertension in the monocrotaline model and suggest a potential therapeutic role for angiogenic factors in the therapy of this devastating disease.

show abstract

PAF receptor blockade inhibits lung vascular changes in the rat monocrotaline model

Cited by 13 publications

References 18 publications

Protective Role of Angiopoietin-1 in Experimental Pulmonary Hypertension

Protective Role of Angiopoietin-1 in Experimental Pulmonary Hypertension

Interleukin-1 receptor antagonist treatment reduces pulmonary hypertension generated in rats by monocrotaline.

Cell-Based Gene Transfer of Vascular Endothelial Growth Factor Attenuates Monocrotaline-Induced Pulmonary Hypertension

Contact Info

Product

Resources

About