Improvement of bleomycin-induced pulmonary hypertension and pulmonary fibrosis by the endothelin receptor antagonist Bosentan.
BACKGROUND
There is evidence that endothelin plays a key role in the development of pulmonary hypertension (PH) in pulmonary fibrosis (PF). However, the functional consequence of the unselective endothelin receptor antagonist Bosentan in PH and PF has not yet been studied. Therefore, we investigated the effects of Bosentan on the development of PH in the model of Bleomycin-induced PF in rats.


METHODS
Adult male Wistar rats were randomly assigned to the following groups: untreated animals (controls), Bleomycin-induced PF (Bleomycin) and Bleomycin-induced PF treated with Bosentan (Bleomycin+Bosentan). Exercise capacity was evaluated by treadmill exercise testing. PH was assessed by right ventricular systolic pressure (RVSP) and right ventricular hypertrophy. For quantification of PF the hydroxyproline content in lung tissue (HPC) was measured.


RESULTS
Compared to controls, animals with Bleomycin-induced PF showed a significant reduction in exercise capacity (44% vs. 100%), significantly higher RVSP (65 mmHg vs. 23 mmHg), significantly more right ventricular hypertrophy (0.55 vs. 0.24) and significantly higher HPC (60.5 vs. 14.8). Bosentan treatment in animals with Bleomycin-induced PF resulted in significantly greater exercise capacity (98% vs. 44%) and a trend towards lower RVSP (52 mmHg vs. 65 mmHg), significantly less right ventricular hypertrophy (0.34 vs. 0.55) and significantly lower HPC (16.7 vs. 60.5) compared to untreated Bleomycin-induced PF.


CONCLUSIONS
Application of Bosentan in Bleomycin rats resulted in significantly higher exercise capacity as a result of improvements in PH and PF.
Schroll
Stephan
S
Department of Internal Medicine II, Pneumology, University of Regensburg, Regensburg, Germany. stephan.schroll@klinik.uni-regensburg.de
Arzt
Michael
M
Sebah
Daniela
D
Nüchterlein
Martin
M
Blumberg
Friedrich
F
Pfeifer
Michael
M
D000704:Analysis of Variance; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001761:Bleomycin / Q000009:adverse effects; D000077300:Bosentan; D003094:Collagen / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D006439:Hemodynamics / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy*; D017380:Hypertrophy, Right Ventricular / Q000188:drug therapy / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D010805:Physical Conditioning, Animal / Q000502:physiology; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy*; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides / Q000627:therapeutic use*; D013997:Time Factors
D000903:Antibiotics, Antineoplastic; D000959:Antihypertensive Agents; C526316:CCN2 protein, rat; D013449:Sulfonamides; D001761:Bleomycin; D055513:Connective Tissue Growth Factor; D003094:Collagen; D000077300:Bosentan