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C21, an AT 2 R agonist, arrests the progression of bleomycin‐induced pulmonary fibrosis and associated cardiac dysfunctions
Author(s) -
Rathinasabapathy Anandharajan,
Horowitz Alana,
Kumar Ashok,
Horton Kelsey,
Martinez Diana,
Raizada Mohan,
Steckelings Ulrike Muscha,
Unger Thomas,
Sumners Colin,
Shenoy Vinayak,
Katovich Michael
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.lb578
Subject(s) - medicine , bleomycin , pulmonary hypertension , fibrosis , lung , pulmonary fibrosis , sirius red , agonist , hydroxyproline , angiology , cardiology , cardiac fibrosis , angiotensin ii , pathology , blood pressure , receptor , chemotherapy
Pulmonary Fibrosis (PF) is a chronic, lethal interstitial lung disease with a median survival of less than 3 years after the onset of disease. PF related mortality necessitates the identification of newer therapeutic targets. We recently observed an imbalance of renin angiotensin system in the pathology of pulmonary hypertension (PH) and demonstrated that utilization of an agonist of the angiotensin type II receptor (AT 2 R) was therapeutically efficacious in not only reducing pulmonary pressure in a rodent model of PH, but it also significantly reduced both pulmonary and cardiac fibrosis in this model. Thus we decided to investigate the therapeutic efficacy of Compound 21, C21, an AT 2 R agonist, in the treatment of PF. A single instillation of Bleomycin (Bleo) in 8‐weeks old rats was used to induce PF. Two weeks after Bleo instillation, Picro Sirius and H&E staining demonstrated significant lung fibrosis (2.99±0.277 vs 17.30±1.36, % of area) and tissue remodeling (1.65±0.183 vs 6.35±0.259, Ashcroft Score). Likewise, hydroxyproline assay demonstrated significant accumulation of collagen in the Bleo‐treated animals (1.82±0.131 vs 4.09±0.665, mM). Extensive tissue remodeling and fibrosis eventually resulted in secondary pulmonary hypertension in the Bleo animals (RVSP; 29.44±0.711 vs 45.72±2.52, mmHg) with concomitant right ventricular hypertrophy (RVH = RV/LV+S; 0.267±0.011 vs 0.400±0.019, wt/wt). Echocardiography (ECHO) assessment demonstrated that ratio of RV/LV (End diastolic Area; 0.307±0.015 vs 0.590±0.034, cm 2 /cm 2 and Ejection Fraction; 0.727±0.014 vs 0.499±0.020, %/%) were significantly dysregulated in the Bleo animals. Two C21 protocols were evaluated. In one (prevention protocol), C21 (0.03 mg/kg) was administered daily for the entire 2 weeks, while in the other (reversal protocol) it was administered after 3 days of Bleo instillation when significant fibrosis and lung tissue remodeling was observed (Picro Sirius; 2.18±0.086 vs 6.58±0.742, % of area and H&E; 1.20±0.079 vs 3.58±0.159, Ashcroft Score). Significant attenuation of lung tissue remodeling, fibrosis, and collagen deposition was observed in both C21 treatment protocols. Furthermore, ventricular hemodynamics (RVSP) and cardiac functions (RVH, RV/LV EDA and EF) were also significantly attenuated in Bleo animals treated with C21. Collectively, the present study demonstrated that the AT 2 R agonist, C21, arrested the progression of PF and the associated cardiac dysfunctions and provides necessary evidence to move forward with a possible AT 2 R‐mediated therapeutic intervention for the treatment of PF. Support or Funding Information This work was supported by NIH grants HL102033, HL056921 and American Heart Association Scientist Development Grant SDG12080302