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Till: COC\CIL 1''Oli'j'013,1CC0 RESI3ARCH=-j:.5.A., I1VC. MarCh 26, 1980 MFMORAHIDLM TD: W. U. Gardner and Staff FROM: D. H. Ford and D. Stone NK®192o001 SUHJE=: Application 1324. Ronald H. Goldstein, M.D., Boston University School of Medi^ine, Mass. "The Structural Integrity of the Aging Lung Connective Tissue Aetwork." SITE VISIT with Drs. Goldstein and C. FYanzblau on March 6, 1980. Drs. Goldstein and Franzblau express the hypothesis that there may be structural changes which occur with increasing age in the supporting pulmonary elastin and aollagen networks which influence the degree of resistance to development of such diseases as enphysena. Conceivably the increased stability of such fibers in old age may be as much due to an increased encasernsnt with protective glycoproteins s.s to an increased cross linkage, as suggested for collagen. Further, there may be differences in the ratios of collagen to elastin or various subaomponents which may also be involved. Since no or little real information on such longitudinally oriented age changes are available to any extent, they would propose to undertake such a study and to deal with changes in total airount of elastin and collagen, changes in rate of synthesis and degradation, as well as differences in the relative amamts of anorph= and microfibrillar elastin present. They have done scme preliminary studies with the hamster using 4- and 15-month old animals and have oUserved that cells fran 15-tnonth old ltmgs have a higher degree of proliferation, which might be due to a breakdown of•the factors involved in contact inhi.bAtion. Fluthes, synthesis of collagen (incorporation of hydroxyprolane) was greater in 15-Ironth thar. 4-nronth old lungs while synthesis of protein (total - uptake of proline) was unchanged. Preliminaty column fraction separation studies demonstrate that there are twn different promllagen peaks which differ in anount present. in this instance, they would plan to deteYmine if the ratio of these twu fractions to each other is oonstant or changes with agn. Other questions to be investigated: 1. They note that elastase solubilizes about 20% of collagen in young animals. Is this constant with increasing age? Elastase treatment leaves insoluble collagen. 2. Are there differences in resistance to injury due to stress between old and young animals? In this instance there is a need to differentiate changes due to age from those due to stress. If there are such changes, they oould,reside in the cells which produce collagen and elastin. A study of this would be undertaken. 3. Are there changes in lung canpliance with age? Suspect there is a fair anount of data on this and it thus oaroes down to relating oampliance changes with potential structural changes.

/1 1411 92N 004 4. Are there changes in pulmonaiy migration of PMs and PAMs which are age-related and could relate to ease of developtinent of pulsmnasy disease? This would be a lavag6 study. 5. Are there changes in d-1 PI and oj-2-M with age? Will collaborate with Dr. P. Stone on this aspect of the project. In this inst,ance, it inay be that the ratio of oC -1 to W,-2 may be mr>re ir.portant than the total amount of each preseat (i.e., hamsters have an a.'-1-PI/oC -2--Pr. ratio of 3:1 while normal humvas have a ratio of about 50:1, and patients with (m#ysena have a ratio of 10:1)o Tt:e suggestion made by Goldstein/Franzblau is that the relative decrease of d-I PI in marn decreases protection against protease, even though ff--2-M renains high, because the c{-2-AfG does not fully block the protease activity. It sews to act as a carrier to transport the enzyme to the liver, ozily partially blocking =ymatic activity against tropelastin and insoluble•elastin. In this sense the A-1 PI/ e(-2-i+2G ratio in the hatnster model resembles more what ie seen in hut;:an emphysena. Thus, if there are subtle changes in the ratio with aging,; the hamster might bocame more susceptible to experimentally-induced emphysana than sane other animal.model. 74'ius, one could test to what degree a change in ratio could influence susceptibility to emphysema. Ctnmeat. Dr. Goldstein appears to be a bright young investigator with considerable enthusiasm but limited experience since he :aas only recently +ocaripleted his training. Dr. Franzblau, of course, has considerable experience in the field of elastin and collagen research and adequate laboratory facilities to conduct the study. Of the various investigators in this field as indicated by the discussions at the Gordon conference last year, little tlwuc~lit has as yet been directed tvward age-related cPianges which could influenee suscept.ibility to anphysemla caused either by increased levels of protease, decreased levels of protein substrates for protease other than collagen or elastin, or changes in the amunts or turnovex rates of collagen and elastin. Thus, the degree to which advancing age may c~ontribute to the developnent of enphysena is tu~ilmown and may be an important factor iu this disease process. In view of our major contributions supporting research in this area and if emphysema is a disease associated with aging, this would be worth supporting. It appears ].ikely that this proposal td:ay well have resulted fran sane of the informal discussions which occurred last s=iex at the Gordon C7ar:ference. Collectively, Drs. Goldstein and Franzblau appear to have the interest, experienee and facility to undertake this study. However, it is to a degree a fishing expedition, but one for %dZich it may be most important to determine the answer inasmuch as changes in any of the possible oomponents of the systeilcould upset what appears a delicate balance and produce enphysena. Tf it were not for the nature of the study, we wrwld recamend an 18-month feasibility study; Ixowever, such an approach would be illogical as saree of the animals would be older than 18 nakths when studied. Therefore, we would recamierxi support but with close monitoring of progz'ess. D. H. k'ord D. Stone /ek Z'