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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

A Noninflammatory Interleukin-1 Fragment Stimulates Fetal Lung Fluid Absorption in Guinea Pigs

Department of Physiology and Pharmacology, Northeastern Ohio Universities College of Medicine, Rootstown, Ohio

We have previously demonstrated that full-length interleukin (IL)-1 can induce and stimulate lung fluid absorption in near-term guinea pig fetuses via stimulation of fetal cortisol synthesis and release. To develop a potentially clinically useful drug, we tested the hypothesis that maternal administration of a noninflammatory IL-1-fragment (IL-1_Fr) induced cortisol synthesis and stimulated lung fluid absorption in preterm fetuses. IL-1_Fr was administered s.c. daily to timed-pregnant guinea pigs for 3 days with and without simultaneous cortisol synthesis inhibition by metyrapone. Fetuses were obtained by abdominal hysterotomy at 61 and 68 days gestation and instilled with isosmolar 5% albumin into the lungs, and lung fluid absorption was measured over 1 h by mass balance. Lung fluid absorption was induced at 61 days and stimulated at 68 days gestation by IL-1_Fr, which both were attenuated by cortisol synthesis inhibition. Moreover, induction of labor by oxytocin stimulated lung fluid absorption at 61 days but had no stimulatory effect at 68 days gestation when given with the IL-1_Fr. Plasma adrenocorticotropin and cortisol concentrations were increased by IL-1_Fr at 61 days gestation and remained high but unstimulated by IL-1_Fr at 68 days gestation, and metyrapone always reduced cortisol concentrations. Prenatal lung fluid absorption, when present as well as IL-1_Fr-induced, was always propranolol- and amiloride-sensitive, suggesting that -adrenoceptor stimulation and the epithelial Na⁺ channel (ENaC) were critical for the induced/stimulated lung fluid absorption. ENaC expression was increased by IL-1_Fr and attenuated by cortisol synthesis inhibition. Thus, our results suggest a potential clinical use of IL-1_Fr therapeutically to induce lung fluid absorption in fetuses at risk of preterm delivery.

Address correspondence to: Dr. Hans G. Folkesson, Professor, Department of Physiology and Pharmacology, Northeastern Ohio Universities College of Medicine, 4209 State Route 44, P.O. Box 95, Rootstown, OH 44272-0095. E-mail: hgfolkes{at}neoucom.edu x100