The overall goal is to investigate the regulation of lipid metabolism in the lung with major emphasis on the lung surfactant system. Sufficient information concerning the pathways of synthesis and nature of the surfactant lipids and apoproteins has been obtained to allow concentration on the regulation processes of individual steps as well as concerted regulation of the system as a whole. In order to be able to identify regulatory steps and perturb the system, lungs from diabetic rats and rats fasted for up to 96 hours will be used. Both of these states are known to cause alterations in the surfactant system. The models for study include the isolated perfused lung, type II epithelial cells in primary culture and importantly, subcellular fractions isolated from type II cells.
The specific aims of the project are: (1) To continue to perform studies to establish in alveolar type II cells the pathways, subcellular location(s) and rate limiting steps in the synthesis of individual lipids of pulmonary surfactant and the regulation of production of each. (2) To initiate studies on the concerted regulation of the synthesis and accumulation of phospholipid components which constitute pulmonary surfactant as it is stored in the lamellar bodies of the type II cell. (3) To investigate at the biochemical level the secretion-reutilization cycle of pulmonary surfactant phospholipids by the type II cells. Reutilization studies will include defining the mechanism of cellular uptake including the specificity of uptake, factors which affect uptake and the fate of the phospholipids which are internalized by the type II cell, including intracellular location of such events. Secretion studies will include the effect of secretory rate on the rate of reutilization of surfactant and the effect of decreased reutilization on the secretory rate. A link between the process of reutilization of surfactant and the """"""""basal"""""""" secretory rate will be explored. And (4) to determine if the identified apoproteins of pulmonary surfactant found on the alveolar surface have a function in the processing, storage, secretions and reutilization of pulmonary surfactant. It is anticipated that the knowledge obtained from these studies will contribute significantly to better clinical care and ultimately prevention of respiratory distress syndrome in the newborn. As well, the knowledge obtained of the individual components of the surfactant system should add to our understanding of the molecular mechanisms involved which may apply to similar processes in other cells.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37HL013405-21
Application #
3485352
Study Section
Metabolism Study Section (MET)
Project Start
1976-09-01
Project End
1991-08-31
Budget Start
1990-09-01
Budget End
1991-08-31
Support Year
21
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Saint Louis University
Department
Type
Schools of Medicine
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63103
Moxley, M A; Baird, T L; Corbett, J A (2000) Adoptive transfer of acute lung injury. Am J Physiol Lung Cell Mol Physiol 279:L985-93
Cai, G Z; Griffin, G L; Senior, R M et al. (1999) Recombinant SP-D carbohydrate recognition domain is a chemoattractant for human neutrophils. Am J Physiol 276:L131-6
Cruz, W S; Corbett, J A; Longmore, W J et al. (1999) Nitric oxide participates in early events associated with NNMU-induced acute lung injury in rats. Am J Physiol 276:L263-8
Cruz, W S; Moxley, M A; Corbett, J A et al. (1997) Inhibition of nitric oxide synthase attenuates NNMU-induced alveolar injury in vivo. Am J Physiol 273:L1167-73
Fleming, R E; Moxley, M A; Waheed, A et al. (1994) Carbonic anhydrase II expression in rat type II pneumocytes. Am J Respir Cell Mol Biol 10:499-505
Anderson, B M; Jackson Jr, F; Moxley, M A et al. (1992) Effects on experimental acute lung injury 24 hours after exogenous surfactant instillation. Exp Lung Res 18:191-204
Moxley, M A; Jacoby, J; Longmore, W J (1991) Uptake and reutilization of surfactant phospholipids by type II cells of isolated perfused lung. Am J Physiol 260:L268-73
Uhal, B D; Longmore, W J (1988) Glycerol as a substrate for phospholipid biosynthesis in type II pneumocytes isolated from streptozotocin-diabetic rats. Biochim Biophys Acta 961:122-8
Uhal, B D; Longmore, W J (1988) Glycerol metabolism in type II pneumocytes isolated from streptozotocin-diabetic rats. Biochim Biophys Acta 958:279-88
Crouch, E C; Moxley, M A; Longmore, W J (1988) Matrix deposition and extracellular processing of newly synthesized collagens in the isolated perfused rat lung. Exp Lung Res 14:705-24

Showing the most recent 10 out of 13 publications