Activation of the selective angiotensin II type 2 receptor agonist (AT2) receptor by Compound 21 (C21) lessens lung damage secondary to bleomycin and reduces cardiopulmonary pathology in rat models, according to a new study published in Frontiers in Physiology.
These results highlight the therapeutic potential of C21 in idiopathic pulmonary fibrosis (IPF) and Group III pulmonary hypertension (PH), which is a classification given by the World Health Organization in patients with comorbid IPF.
“Despite scientific advances, the dismal prognosis of IPF and associated PH remains unchanged, necessitating the search for novel therapeutic strategies,” wrote primary author, Anandharajan Rathinasabapathy, PhD, Department of Pharmacodynamics, University of Florida, Gainesville, FL. “Accumulating evidence suggests that stimulation of the angiotensin II type 2 (AT2) receptor confers protection against a host of diseases.”
Specifically, experts have shown that C21-induced agonism of the AT2 receptor in experimental models protects against kidney damage, heart attack, ischemic stroke, and islet cell damage. In a previous study, Dr. Rathinasabapathy and colleagues found that the administration of C21 stops the pathogenesis of monocrotaline-induced PH—effects which are reversed by the co-administration of PD123319, an AT2-receptor antagonist.
In the current study, the investigators looked at the clinical potential of C21 vs lung fibrosis and concomitant cardiopulmonary complications in rat models with bleomycin-induced lung injury. On intratracheal challenge with bleomycin, these animal models mirror the disease features of humans with IPF plus PH.
The authors induced lung fibrosis and PH in 8-week-old male Sprague Dawley rats using bleomycin (2.5 mg/kg). They then followed two separate protocols. In the first, they administered a 0.03 mg/kg/day intraperitoneal C21 injection immediately after giving bleomycin (ie, the prevention protocol). In the second, they administered this C21 injection 3 days after giving bleomycin (ie, the treatment protocol).
The investigators then performed echocardiography, hemodynamic, and Fulton’s index assessments 2 weeks following instillation of bleomycin. Furthermore, they processed lung tissue for gene expression, hydroxyproline content, and histology. Of note, hydroxyproline content is a biomarker indicative of collagen deposition.
Results showed that C21 had the following significant effects in rat models with bleomycin-induced lung damage:
- Reduced PH and decreased muscularization of the pulmonary vessels, along with restoring cardiac function
- Prevented and attenuated the progression of PF by reducing extracellular matrix remodeling and lung collagen accumulation
- Alleviated inflammatory stress by reducing the infiltration of lung macrophages
Outcomes were equivalent in both the prevention and treatment protocols.
On the basis of these findings, the team suggests that the synthetic activator C21 may be of clinical use in patients with PF and comorbid Group III PH.
C21 not only lessened bleomycin-induced cardiac hypertrophy, but it also ameliorated right heart function. Dr. Rathinasabapathy and co-authors suggest that the protective actions of C21 may arise from either a reduction in fibrotic injury or from the direct actions of C21 on the heart.
“Collectively, our study provides the necessary experimental evidence to attempt the strategy of utilizing AT2 receptor agonist for the treatment of IPF and Group III PH,” the researchers concluded.
To read more about this study, click here.