M.Sc Thesis

M.Sc StudentKnany Yara
SubjectThe Involvement of Corin and Natriuretic Peptide System in
Alveolar Fluid Clearance in Heart Failure Model
DepartmentDepartment of Medicine
Supervisors PROF. Zaher Azzam
PROF. Zaid A. Abassi


Introduction: Active alveolar fluid clearance (AFC) is important for keeping the airspaces free of edema, mainly due to the contribution of alveolar epithelial Na,K-ATPase pump and Na channels (ENaC). The edema clearance process can be modulated by atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). Corin, a cardiac serine protease, is responsible for converting pro-ANP and pro-BNP to biologically active natriuretic peptides (NPs). Although, it has been reported that ANP increased alveolar epithelial permeability and attenuated AFC; little is known about the underlying molecular mechanisms of the inhibitory effects of NPs on AFC.

Aims: To examine ANP and BNP contribution to alveolar fluid clearance process, and their role affecting alveolar active sodium transport in health and heart failure.

Methods & Results: By using the isolated liquid filled-lungs model, we have investigated the effect of ANP and BNP on AFC rate. ANP and BNP decreased active Na transport and impeded alveolar fluid clearance, by downregulating the active Na transport in the alveolar epithelium, alongside with enhancing the ubiquitination and the degradation of αENaC in the lungs; by upregulating the Nedd4-2 levels. In addition, our data indicated that ANP and BNP activate ER-stress response and induce autophagy in lung tissue.

Congestive heart failure (CHF) often leads to salt/water retention as evident by peripheral and lung edema. Although the involvement of corin and natriuretic peptides in heart failure was extensively studied, NPs role in inducing lung edema in CHF patients have not been studied. Thus in this study we have investigated the involvement of ANP on AFC process in CHF rats.  We demonstrated that in compensated CHF, ANP decreased AFC rate, by enhancing the ubiquitination of ENaC in the apical membrane. While, ANP administration to the lungs of decompensated CHF rats, partially restored the ability of the lungs to clear edema.

Conclusions: We herein suggest a novel mechanism of clinical relevance of which ANP and BNP adversely impair the ability of lungs to clear edema. Furthermore, in light of the ANP ability to enhance the AFC in decompensated CHF, we postulate that these findings may serve as a basis for improvement pharmacological therapy of CHF especially in severe cases.