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Structural and biochemical aspects of postnatal lung growth in experimental diabetes : the role of endogenous factors Ofulue, Anwuli Felix

Abstract

The effect of experimental diabetes on the lung was studied in male rats made diabetic by injecting streptozotocin at age 3 weeks and sacrificed at age 7 weeks. Since the diabetic animals showed poor weight gain, an undernourished control group of similar weight gain was instituted, giving the opportunity to simultaneously study the effect of undernourishment. The other groups studied were normal control animals with access to food ad libitum and diabetic animals treated with insulin. The diabetic animals weighed 75% of the fed control but specific lung weight and lung volume were increased. These changes were associated with increased number and surface area of alveoli, decreased size of alveoli, increased collagen and elastin content although the rate of synthesis appeared normal,and decreased cell number but normal cell size. In contrast, the undernourished control animals had normal specific lung weight and lung volume associated with decreased alveolar number and surface area but increased size of alveoli, decreased content and synthesis of collagen and elastin, reduced cell number and cell size. The changes in the insulin-treated diabetic animals were midway between the values of normal control and untreated diabetic animals. In the lungs of all the experimental groups of animals, there was a positive relationship between the changes in connective tissue content and those in alveolar number; cellular proliferation was unrelated to alveolar number. Such finding supports the hypothesis that connective tissue deposition rather than cellular proliferation is the major determinant of alveolar formation and maturation. In vitro studies indicated that soluble lung extracts derived from the experimental animals had suppressive effects on DNA and connective tissue syntheses by normal lung mince in culture. The extracts of the undernourished control animals were more potent than those of the other experimental groups, and this appeared to be due to the increased activity of an adenylate cyclase cytosolic modulator present in the lung. The suppressive effect on connective tissue production by the extracts of the diabetic animals was less than those of the other animals, and this was apparently due to the reduced activity of a heat-stable 13700-17000 dalton protein probably associated with the ubiquitous Ca²⁺-dependent regulatory protein known as calmodulin. The reduced cellular proliferation in the lungs of the diabetic animals was due mostly to a heat-stable 17000-25000 dalton protein which suppressed the ability of calmodulin to enhance DNA synthesis. The data indicate that changes in the activities of these endogenous factors mediated at least in part the structural changes observed in the lung in response to undernourishment and experimental diabetes.

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