The role of the natriuretic peptide pathway in the control of surfactant release from fetal and newborn alveolar type II cells

The natriuretic peptides (NP) are a family of small peptide hormones, which possess a wide array of paracrine and endocrine functions throughout the body. The NP family is comprised of atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP) and C-type natriuretic peptide (CNP). The activity of the natriuretic peptides are mediated through their binding to specific membrane bound receptors---ANP and BNP bind to the natriuretic peptide A receptor (NPR-A) while CNP binds the natriuretic peptide B receptor (NPR-B). The binding of the NPs to NPR-A or NPR-B activates an intracellular guanylyl cyclase domain that catalyzes the conversion of GTP to the second messenger cGMP. A third non-guanylyl cyclase linked NP receptor NPR-C, has roughly equal affinity for all three NPs and has been shown recently to be a negative regulator of adenylyl cyclase. Previous studies have demonstrated that the natriuretic peptides are capable of regulating alveolar type II (ATII) cell function in the adult, however its role in the fetal and newborn lung has not been investigated. An essential function of ATII cells at birth is the production of surfactant, a substance responsible for establishing and maintaining low surface tension in the alveolus. In order to define the role of the NP in the regulation of surfactant during the perinatal period we first mapped the protein expression of the NP and NPR in the developing lung using immunohistochemistry. Secondly, the effect of NPR stimulation on surfactant release from ATII cells was assessed using a novel in vitro method developed by our laboratory. All three NPs and NPR are expressed in ATII of late gestational age fetal lambs and decrease dramatically after birth. In vitro, the stimulation of NPR-A by ANP (100pM) increased surfactant release from ATII cells. Higher doses of ANP (1uM) and the NPR-C specific agonist C-ANP (4-23) did not alter surfactant release. However, both C-ANP (4-23) and ANP (1uM) significantly blunted terbutaline-stimulated surfactant release. The present data indicate a dual role for ANP in the developing lung: (1) stimulation of surfactant release occurring through the activation of NPR-A and (2) NPR-C mediated inhibition of beta agonist-stimulated surfactant release. Based on these findings, we speculate that alterations in ATII cell NP and NPR expression in the immediate newborn period modulate surfactant release and aid in the transition to air breathing.