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. 2010 Mar 31;11(1):36.
doi: 10.1186/1465-9921-11-36.

Role of chymase in cigarette smoke-induced pulmonary artery remodeling and pulmonary hypertension in hamsters

Tao Wang  1 , Su-Xia Han, Shang-Fu Zhang, Yun-Ye Ning, Lei Chen, Ya-Juan Chen, Guang-Ming He, Dan Xu, Jin An, Ting Yang, Xiao-Hong Zhang, Fu-Qiang Wen
Affiliations

Role of chymase in cigarette smoke-induced pulmonary artery remodeling and pulmonary hypertension in hamsters

Tao Wang et al. Respir Res. .

Abstract

Background: Cigarette smoking is an important risk factor for pulmonary arterial hypertension (PAH) in chronic obstructive pulmonary disease (COPD). Chymase has been shown to function in the enzymatic production of angiotensin II (AngII) and the activation of transforming growth factor (TGF)-beta1 in the cardiovascular system. The aim of this study was to determine the potential role of chymase in cigarette smoke-induced pulmonary artery remodeling and PAH.

Methods: Hamsters were exposed to cigarette smoke; after 4 months, lung morphology and tissue biochemical changes were examined using immunohistochemistry, Western blotting, radioimmunoassay and reverse-transcription polymerase chain reaction.

Results: Our results show that chronic cigarette smoke exposure significantly induced elevation of right ventricular systolic pressures (RVSP) and medial hypertrophy of pulmonary arterioles in hamsters, concurrent with an increase of chymase activity and synthesis in the lung. Elevated Ang II levels and enhanced TGF-beta1/Smad signaling activation were also observed in smoke-exposed lungs. Chymase inhibition with chymostatin reduced the cigarette smoke-induced increase in chymase activity and Ang II concentration in the lung, and attenuated the RVSP elevation and the remodeling of pulmonary arterioles. Chymostatin did not affect angiotensin converting enzyme (ACE) activity in hamster lungs.

Conclusions: These results suggest that chronic cigarette smoke exposure can increase chymase activity and expression in hamster lungs. The capability of activated chymase to induce Ang II formation and TGF-beta1 signaling may be part of the mechanism for smoking-induced pulmonary vascular remodeling. Thus, our study implies that blockade of chymase might provide benefits to PAH smokers.

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Figures

Figure 1
Figure 1
Cigarette smoke-induced changes in pulmonary vascular and alveolar morphology and right ventricular systolic pressure (RVSP). (a) Representative hematoxylin and eosin (H&E) staining of small pulmonary vessels (original magnification × 40). (b) Representative Masson's trichrome staining of small pulmonary vessels (original magnification × 40). (c) Emphysema-like lesions in the lung after smoke exposure (H&E staining, original magnification × 20). (d) Medial wall thickness (MWT) of pulmonary arterioles. (e) RVSP in hamsters. Con: control group; CS: cigarette smoke-exposed group. Scale bars = 100 μm. Values are expressed as mean ± SD (n = 6). * P < 0.05, significant difference from the control group.
Figure 2
Figure 2
Changes in chymase protein and mRNA levels in hamster lungs. (a) Representative chymase immunohistochemical staining in pulmonary arterioles (original magnification × 40). (b) Representative Western blotting analysis of chymase protein levels in hamster lungs. (c) Representative RT-PCR analysis of chymase mRNA levels in hamster lungs. Con: control group; CS: cigarette smoke-exposed group. Scale bars = 100 μm. Data are expressed as mean ± SD (n = 3 for control group and n = 4 for smoke-exposed group). * P < 0.05, significant difference from the control group.
Figure 3
Figure 3
Changes of chymase-like and ACE activities after chymase inhibition with chymostatin in hamster lungs. (a) Chymase-like activity. (b) ACE activity. Control: control group; CS: cigarette smoke-exposed group; 1 mg/kg Chymo: hamsters treated with 1 mg/kg chymostatin alone; 2 mg/kg Chymo: hamsters treated with 2 mg/kg chymostatin alone; CS + 1 mg/kg Chymo: hamsters treated with cigarette smoke plus 1 mg/kg Chymostatin; CS + 2 mg/kg Chymo: hamsters treated with cigarette smoke plus 2 mg/kg Chymostatin. Values are expressed as mean ± SD (n = 6). * P < 0.05, significant difference from the control group. # P < 0.05, significant difference from the smoke-exposed group.
Figure 4
Figure 4
Changes in the remodeling of pulmonary arterioles and RVSP after chymase inhibition with chymostatin. (a) Representative van Gieson's elastic staining of small pulmonary vessels (original magnification × 40). Scale bars = 100 μm. Con: control; CS: cigarette smoke exposure; Chy: treatment with 2 mg/kg chymostatin alone; CS+Chy: treatment with smoke exposure plus 2 mg/kg chymostatin. (b) MWT of pulmonary arterioles. (c) RVSP. Control: control group; CS: cigarette smoke-exposed group; Chymo: chymostatin treatment. Values are expressed as mean ± SD (n = 6). * P < 0.05, significant difference from the control group. # P < 0.05, significant difference from the smoke-exposed group.
Figure 5
Figure 5
Changes in Ang II levels and TGF-β1/Smad signaling activation in hamster lungs. (a) Ang II levels. Values are expressed as mean ± SD (n = 6). (b) Protein levels of TGF-β1, β-actin, p-Smad2, Smad2, p-Smad3 and Smad3 measured by Western blotting analysis. Images are representative of three independent experiments. Relative protein levels were assessed by densitometry. Control: control group; CS: cigarette smoke-exposed group; Chymo: chymostatin treatment. * P < 0.05, significant difference from the control group. # P < 0.05, significant difference from the smoke-exposed group.
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