Reactive Oxygen Species and Substance P in Monocrotaline-Induced Pulmonary Hypertension

Chen, Mei‐Jyh; Chiang, Long Y.; Lai, Yih‐Loong

doi:10.1006/taap.2000.9117

Cited by 30 publications

(24 citation statements)

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“…In monocrotaline-induced PH, ROS were shown to increase the levels of SP [9]. The results of this study show that oxygen radicals are generated upon either exposure of PCLS to severe hypoxia or low doses of [Sar Proliferation of vascular cells occurred only in small (v50 mm), resistance-type vessels, which is the part of the pulmonary vascular bed responsible for the pressure elevation observed in PH [3].…”

Section: Discussionmentioning

confidence: 75%

“…Groups of six animals were incubated for 1 h in the presence of 1 mM DCF-DA and gassed with 21 or 1% O 2 . Under both O 2 conditions, 5 nM [Sar 9 ,Met 11 (O 2 )]-SP, in the presence and absence of the nonpeptide NK-1 receptor antagonist CP 96345 (1 mM), was added. Control sections were incubated with 1 mM CP 96345 or MEM alone.…”

Section: Tissue Processingmentioning

confidence: 99%

“…6b and c). In lung sections incubated with [Sar 9 ,Met 11 (O 2 )]-SP under normoxic conditions, HIF-1a was detected in the parenchyma, as well as a small number of vessels ( fig. 6c), whereas larger vessels did not display any HIF-1a stabilisation (data not shown).…”

Section: Detection Of Hypoxia Inducible Factor-1amentioning

confidence: 99%

“…While the vasodilator response has been shown to be mediated through activation of the NK-1 receptor and release of NO and prostacyclins [8], the mechanism of SP-induced remodelling remains unclear. In a rat model of monocrotaline-induced inflammation of pulmonary vessels, ROS were suggested to increase levels of SP [9], possibly by inactivation of the SP-degrading enzyme neutral endopeptidase (EC 3.4.24.11).Due to the similarities of hypoxia and SP-induced vascular remodelling and PH, the hypothesis that SP exerts its effects by generating ROS was addressed in this study. Using precision cut lung slices (PCLS) of mice as a model, the effects of SP on ROS generation and HIF-1a stabilisation, as well as the effects on proliferation in pulmonary vessels, were examined.…”

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Substance P‐induced pulmonary vascular remodelling in precision cut lung slices

Springer¹,

Fischer²

2003

Eur Respir J

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Substance P-induced pulmonary vascular remodelling in precision cut lung slices. J. Springer, A. Fischer. #ERS Journals Ltd 2003. ABSTRACT: Substance P (SP) levels have been reported to be elevated in animal models of pulmonary hypertension (PH) and chronic administration of SP has been shown to induce PH. In the present study, the role of reactive oxygen species (ROS) as mediators of SP-induced vascular remodelling and PH was analysed.Vascular The pathophysiological pathways involved in the development of primary pulmonary hypertension (PH) and of the more common secondary PH are still unclear. A common feature of all forms of PH is pulmonary vascular remodelling and right ventricular hypertrophy. The main cause for PH in humans is alveolar hypoxia [1] as a result of chronic lung diseases leading to secondary PH [2]. Hypoxia induces the generation of reactive oxygen species (ROS) in various cells, including pulmonary vascular smooth muscle cells (VSMC), and causes proliferation of VSMCs and adventitial fibroblasts [3]. The mechanism involves the ubiquitously expressed, hypoxia sensitive transcription factor hypoxia inducible factor (HIF)-1a, which is stabilised by ROS [1]. HIF-1a activation is maximal at an oxygen (O 2 ) concentration of 0.5-2% [4], whereas it is rapidly degraded by the ubiquitinproteasome pathway under normoxic conditions [5].Several observations suggest that substance P (SP) is involved in the pathophysiological events leading to the vascular remodelling observed in PH. Pharmacological application of a stable SP analogue induces vascular remodelling, leading to thickening of the media and to the development of PH in rats, while pretreatment with the tachykinin NK-1 receptor antagonist CP 96345 has been shown to prevent SPinduced PH [6]. In patients suffering from PH, SP fails to cause the marked endothelium-dependent vasodilatation that is observed in healthy subjects [7]. While the vasodilator response has been shown to be mediated through activation of the NK-1 receptor and release of NO and prostacyclins [8], the mechanism of SP-induced remodelling remains unclear. In a rat model of monocrotaline-induced inflammation of pulmonary vessels, ROS were suggested to increase levels of SP [9], possibly by inactivation of the SP-degrading enzyme neutral endopeptidase (EC 3.4.24.11).Due to the similarities of hypoxia and SP-induced vascular remodelling and PH, the hypothesis that SP exerts its effects by generating ROS was addressed in this study. Using precision cut lung slices (PCLS) of mice as a model, the effects of SP on ROS generation and HIF-1a stabilisation, as well as the effects on proliferation in pulmonary vessels, were examined. PLCS combine the advantages of cell culture in an organoid system. They are mostly used for pharmacological [10,11] or toxicological studies and allow the use of human tissue (for review see [12]). Methods Tissue processingAfter killing the animals by cervical dislocation, 500 U heparine (Hoffmann-La Roche, Grenzach-Wyhlen, Germany) and 1 mM glyceryltrinitrate ...

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Section: Discussionmentioning

confidence: 75%

Section: Tissue Processingmentioning

confidence: 99%

Section: Detection Of Hypoxia Inducible Factor-1amentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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