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Memorandum To: Dr. J. F. Glenn and Staff From: D.H.Ford Re: Site visit with Dr. W. Rice,niversity of Cincinnati Medical Center, March 28, 1988. Grant Entitled "Neuropeptide hormone regulation-of surfactant secretion,"Grant No. 1919R1. Goal: To determine if substance P or some.other ligand regulates the release of surfactant, in a culture system. Results: The studies utiliz•ing Sub P in Type II cell cultures revealed that njither Sub P or any of its analogues inhibited the release of H-phosphatidylcholine from the cells, even though Sub.P bound to a receptor on the cells. It subsequently turned out that Sub P was binding to a receptor which bound a major surfactant- associated protein.(SAP-35), with.a molecular weight of 35 kD. By its molecular structure it appears to be some form of a collagen lectin hybrid. This protein was then shown to inhibit the release of surfactant from the lamellar bodies. Thus, the surfactant molecule itself carries the ligand which will turn off secretion, a form of autoregulation. So far his studies indicate that the, carbohydrate component of the molecule is not important for inhibition of secret- ion. The importance of this regulation would be that failure of inhibition would lead to an excess production of surfactant, causing an accum- ulation of protein :-in the alveoli, inflammation, with accumulations of PMN cells, release of protease and emphysema. Questions remaining to'be answered are: What are the components of the second messenger system (transduction) +Vch turn off secretion? (Perhaps ATP, an agonist which mobilizes Ca in Type II cells). Other possibilities relate to some response of the cytoskeleton or an inhibition of protein kinase C and the role of phosphorylation. Further, if SAP-35 is the 'turn-off' ligand, what initiates secretion? Perhaps an agonist is not needed in that the cell may continuously function to release surfactant and only needs a negative regulation to depress it. Comment: An interesting investigation relevent to COPD and emphysema conducted by an energetic, knowledgable investigator. He appears to focus his energies to the problems of pulmonary pathology with a specific interest in the neonate. His program continues to be relevent to,the interests of CTR, and, since his continued interest is in the subsequent transductive events following binding of SAP-35 to the receptor, this program would appear to merit continued support. DHF