Alamandine: A promising treatment for fibrosis.

Angiotensin (Ang) II, the main active member of the renin angiotensin system (RAS), is essential for the maintenance of cardiovascular homeostasis. However, hyperactivation of the RAS causes fibrotic diseases. Ang II has pro-inflammatory actions, and moreover activates interstitial fibroblasts and/or dysregulates extracellular matrix degradation. The discovery of new RAS pathways has revealed the complexity of this system. Among the RAS peptides, alamandine (ALA, Ala1 Ang 1-7) has been identified in humans, rats, and mice, with protective actions in different pathological conditions. ALA has similar effects to its well-known congener, Ang-(1-7), as a vasodilator, anti-inflammatory, and antifibrotic. Its protective role against cardiovascular diseases is well-reviewed in the literature. However, the protective actions of ALA in fibrotic conditions have been little explored. Therefore, in this article, we review the ability of ALA to modulate the inflammatory process and collagen deposition, to serve as an antioxidant, and to mediate protection against functional disorders. In this scenario, we also explore ALA as a promising therapy for pulmonary fibrosis after COVID-19 infection.

Assessment of Alamandine in Pulmonary Fibrosis and Respiratory Mechanics in Rodents.

INTRODUCTION: Pulmonary fibrosis (PF) is characterized by an accelerated decline in pulmonary function and has limited treatment options. Alamandine (ALA) is a recently described protective peptide of the renin-angiotensin system (RAS) with essential tasks in several conditions. Our group previously demonstrated that ALA is reduced by 365% in the plasma of patients with idiopathic PF, and thus, it is plausible to believe that stimulation of this peptide could represent an important therapeutic target. In this sense, this study investigates the effects of ALA in an experimental model of PF. MATERIALS AND METHODS: Bleomycin (BLM) was administrated in Wistar rats, and these fibrotic animals were treated with ALA for 14 days. Body weight, histology, respiratory, and hemodynamic parameters were analyzed to study the effects of ALA. RESULTS: ALA treatment attenuated the development of fibrosis (P < 0.0001), reduced respiratory system elastance (P < 0.0001), and preserved weight gain (P < 0.0001) in fibrotic animals without affecting the autonomic control of blood pressure and heart rate. CONCLUSION: The data from this study demonstrate the potential of ALA to alleviate pulmonary fibrosis and improve respiratory system mechanics in vivo. The promising results encourage more detailed investigations of the potential of ALA as a future and efficient antifibrotic.

Impact of angiotensin II type 1 and G-protein-coupled Mas receptor expression on the pulmonary performance of patients with idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a severe interstitial disease with a mean survival of about 2.5-5 years after diagnosis. Its pathophysiology is still a major challenge for science. It is known that angiotensin II (Ang-II) binds AT1 receptor (AT1R) and its overactivation induces fibrosis, inflammation and oxidative stress. In contrast, activation of the Mas receptor (Mas-R) by angiotensin 1-7 opposes the harmful effects induced by Ang-II. Thus, our innovative objective was to analyze, in patients' lung with IPF, the balance between AT1R and Mas-R expression and their possible association with pulmonary spirometric parameters: forced expiratory volume in the first second (FEV1%) and forced vital capacity (FVC%). One cubic centimeter of lung tissue was obtained from IPF patients (n = 6) and from patients without IPF (n = 6) who underwent bronchial carcinoma resection. Receptor expression was quantified using western blot. AT1R expression was significantly higher (34 %) in patients with IPF (P = 0.006), whereas Mas-R was significantly less expressed (54 %) in these patients' lungs (P = 0.046). There was also a positive correlation between Mas-R expression and FEV1% (r = 0.62, P = 0.03) and FVC% (r = 0.58, P = 0.05). Conversely, AT1R expression was negatively correlated with FEV1% (r = 0.80, P = 0.002) and FVC% (r = 0.74, P = 0.006). In conclusion, our results demonstrated an increased expression of AT1R and reduced expression of Mas-R in the lung of patients with IPF. The dominance of AT1R expression is associated with reduced lung function, highlighting the role of the renin-angiotensin system peptides in the pathophysiology of IPF.