Abstract
Idiopathic Pulmonary Fibrosis (IPF) is a chronic lung disease characterized by scar formation and respiratory insufficiency, which progressively leads to death. Pulmonary hypertension (PH) is a common complication of IPF that negatively impacts clinical outcomes, and has been classified as Group III PH. Despite scientific advances, the dismal prognosis of IPF and associated PH remains unchanged, necessitating the search for novel therapeutic strategies. Accumulating evidence suggests that stimulation of the angiotensin II type 2 (AT2) receptor confers protection against a host of diseases. In this study, we investigated the therapeutic potential of Compound 21 (C21), a selective AT2 receptor agonist in the bleomycin model of lung injury. A single intra-tracheal administration of bleomycin (2.5 mg/kg) to 8-week old male Sprague Dawley rats resulted in lung fibrosis and PH. Two experimental protocols were followed: C21 was administered (0.03 mg/kg/day, ip) either immediately (prevention protocol, BCP) or after 3 days (treatment protocol, BCT) of bleomycin-instillation. Echocardiography, hemodynamic, and Fulton's index assessments were performed after 2 weeks of bleomycin-instillation. Lung tissue was processed for gene expression, hydroxyproline content (a marker of collagen deposition), and histological analysis. C21 treatment prevented as well as attenuated the progression of lung fibrosis, and accompanying PH. The beneficial effects of C21 were associated with decreased infiltration of macrophages in the lungs, reduced lung inflammation and diminished pulmonary collagen accumulation. Further, C21 treatment also improved pulmonary pressure, reduced muscularization of the pulmonary vessels and normalized cardiac function in both the experimental protocols. However, there were no major differences in any of the outcomes measured from the two experimental protocols. Collectively, our findings indicate that stimulation of the AT2 receptor by C21 attenuates bleomycin-induced lung injury and associated cardiopulmonary pathology, which needs to be further explored as a promising approach for the clinical treatment of IPF and Group III PH.
Highlights
Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive interstitial lung disease with a median survival of 3 years after diagnosis (Raghu et al, 2011)
We have recently reported that treatment with Compound 21 (C21) (0.03 mg/kg/day, ip) after the establishment of disease pathogenesis effectively arrests the progression of monocrotaline-induced Pulmonary hypertension (PH), and these beneficial effects are abolished by co-administration of the Angiotensin type 2 (AT2) receptor antagonist, PD123319 (Bruce et al, 2015)
The most significant finding of the present work is that pharmacological activation of the AT2 receptor by C21 effectively mitigates pulmonary fibrosis (PF), and improves cardiopulmonary complications in an experimental model of bleomycin-induced lung injury
Summary
Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive interstitial lung disease with a median survival of 3 years after diagnosis (Raghu et al, 2011). Nintedanib (inhibits multiple tyrosine kinase) and pirfenidone (downregulates transforming growth factor β) are the only drugs approved for IPF treatment (Raghu and Selman, 2015). They provide little therapeutic efficacy, fail to prolong survival, and are associated with increased incidence of side effects (Canestaro et al, 2016). All these factors necessitate the search for novel strategies to effectively combat IPF and associated cardiopulmonary symptoms
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