Received for publication July 25, 2006.
Revised November 13, 2006.
Accepted for publication November 13, 2006.

A non-inflammatory IL-1-fragment (IL-1_Fr) stimulates fetal lung fluid absorption in guinea pigs

Abstract

We have previously demonstrated that full-length IL-1 can induce and stimulate lung fluid absorption in near-term guinea pig fetuses via stimulation of fetal cortisol synthesis and release. In order to develop a potentially clinically useful drug, we tested the hypothesis that maternal administration of a non-inflammatory IL-1-fragment (IL-1_Fr) induced cortisol synthesis and stimulated lung fluid absorption in preterm fetuses. IL-1_Fr was administered subcutaneously daily to timed-pregnant guinea pigs for three days with and without simultaneous cortisol synthesis inhibition by metyrapone. Fetuses were obtained by abdominal hysterotomy at 61 and 68 days (D) 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 61D and stimulated at 68D gestation by IL-1_Fr, which both were attenuated by cortisol synthesis inhibition. Moreover, labor-induction by oxytocin stimulated lung fluid absorption at 61D, but had no stimulatory effect at 68D gestation when given with the IL-1_Fr. Plasma ACTH and cortisol concentrations were increased by IL-1_Fr at 61D gestation, remained high but unstimulated by IL-1_Fr at 68D 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 AR-stimulation and 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.

Key words: ENaC, alveolar fluid clearance, amiloride-sensitive Na channels, cortisol, lung maturation, oxytocin-induced labor