Alveolar surfactant is a complex mixture of lipids and proteins. Surfactant is synthesized in alveolar type II cells and stored in unique subcellular organelles called lamellar bodies until it is secreted into the airspace. The most well established function of surfactant is to reduce surface tension at the air-liquid interface, thereby preventing lung collapse. A deficiency of surfactant in premature newborns is a primary cause of Respiratory Distress Syndrome. It has also been suggested that a deficit of surfactant or its inactivation may be involved in adult lung diseases. Although the synthesis and secretion of surfactant have been extensively studied, far less is known about the factors that regulate surfactant clearance. In the steady-state condition, the secretion and clearance of surfactant must be balanced so that an appropriate amount of functional surfactant is available to reduce surface tension. Studies from this and other laboratories suggest that the alveolar type II cell can internalize surfactant and incorporate it into the lamellar bodies, where the surfactant is stored until it is eventually resecreted. This """"""""recycling' pathway has been calculated to account for 25 to 90% of alveolar clearance. The long term objective of the proposed work is to study the factors that regulate surfactant clearance. Recent work from this laboratory suggests that the major surfactant protein SP-A (Mr=26,000-36,000) may play an important role in regulating surfactant pool size and metabolism. SP-A enhances uptake of surfactant lipids by type II cells. SP-A also appears to influence the metabolism of internalized lipid: lipid that are internalized in the absence of SP-A are degraded to a greater extent than are lipids that are internalized in the presence of SP-A. SP-A can inhibit the stimulated secretion of surfactant lipid by isolated type II cells. I am hypothesizing that SP-A plays an important role in the feedback regulation of alveolar surfactant pool size by balancing secretion and reuptake via a receptor-mediated interaction with type II cells and perhaps macrophages, and that SP-A may be involved in the regulation of the metabolism (i.e., recycling or degradation) of internalized surfactant lipids. The five specific aims of this proposal are: 1) To determine if type II cells express a receptor for SP-A, and to isolate and characterize the putative receptor; 2) to study the mechanism of interaction of SP-A with type II cells by a) determining the domain of SP-A that binds to the cells and by) by modifying SP-A both chemically and with recombinant DNA technology; 3) To study the metabolism of endocytosed SP-A; 4) To trace the movement of internalized surfactant lipids and proteins through intracellular pathways in type II cells by electronmicroscopic autoradiography and isolation of subcellular organelles; and 5) To characterize further the interaction of SP-A with alveolar macrophages.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL030923-09
Application #
3341930
Study Section
Respiratory and Applied Physiology Study Section (RAP)
Project Start
1983-07-01
Project End
1994-06-30
Budget Start
1991-07-15
Budget End
1992-06-30
Support Year
9
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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Mukherjee, Sambuddho; Giamberardino, Charles; Thomas, Joseph et al. (2012) Surfactant protein A integrates activation signal strength to differentially modulate T cell proliferation. J Immunol 188:957-67
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Geunes-Boyer, Scarlett; Heitman, Joseph; Wright, Jo Rae et al. (2010) Surfactant protein D binding to Aspergillus fumigatus hyphae is calcineurin-sensitive. Med Mycol 48:580-8
Geunes-Boyer, Scarlett; Oliver, Timothy N; Janbon, Guilhem et al. (2009) Surfactant protein D increases phagocytosis of hypocapsular Cryptococcus neoformans by murine macrophages and enhances fungal survival. Infect Immun 77:2783-94
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Zaas, David W; Swan, Zachary D; Brown, Bethany J et al. (2009) Counteracting signaling activities in lipid rafts associated with the invasion of lung epithelial cells by Pseudomonas aeruginosa. J Biol Chem 284:9955-64

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