Hans G. Folkesson

Stimulation of MAP kinase pathways after maternal IL-1β exposure induces fetal lung fluid absorption in guinea pigs

BackgroundWe tested the hypothesis that maternal interleukin-1β (IL-1β) pretreatment and induction of fetal cortisol synthesis activates MAP kinases and thereby affects lung fluid absorption in preterm guinea pigs.MethodsIL-1β was administered subcutaneously daily to timed-pregnant guinea pigs for three days. Fetuses were obtained by abdominal hysterotomy and instilled with isosmolar 5% albumin into the lungs and lung fluid movement was measured over 1 h by mass balance. MAP kinase expression was measured by western blot.ResultsLung fluid absorption was induced at 61 days (D) gestation and stimulated at 68D gestation by IL-1β. Maternal IL-1β pretreatment upregulated ERK and upstream MEK expression at both 61 and 68D gestation, albeit being much more pronounced at 61D gestation. U0126 instillation completely blocked IL-1β-induced lung fluid absorption as well as IL-1β-induced/stimulated ERK expression. Cortisol synthesis inhibition by metyrapone attenuated ERK expression and lung fluid absorption in IL-1β-pretreated fetal lungs. JNK expression after maternal IL-1β pretreatment remained unaffected at either gestation age.ConclusionThese data implicate the ERK MAP kinase pathway as being important for IL-1β induction/stimulation of lung fluid absorption in fetal guinea pigs.

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

We have previously demonstrated that full-length interleukin (IL)-1β 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-1β-fragment (IL-1βFr) induced cortisol synthesis and stimulated lung fluid absorption in preterm fetuses. IL-1βFr 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-1βFr, 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-1βFr. Plasma adrenocorticotropin and cortisol concentrations were increased by IL-1βFr at 61 days gestation and remained high but unstimulated by IL-1βFr at 68 days gestation, and metyrapone always reduced cortisol concentrations. Prenatal lung fluid absorption, when present as well as IL-1βFr-induced, was always propranolol- and amiloride-sensitive, suggesting that β-adrenoceptor stimulation and the epithelial Na+ channel (ENaC) were critical for the induced/stimulated lung fluid absorption. ENaC expression was increased by IL-1βFr and attenuated by cortisol synthesis inhibition. Thus, our results suggest a potential clinical use of IL-1βFr therapeutically to induce lung fluid absorption in fetuses at risk of preterm delivery.

Alveolar Epithelial Fluid Transport in Lung Injury

This chapter discusses the regulation of lung fluid transport by lung epithelial active ion transport mechanisms. Ion transport occurs across both the alveolar and the distal airway epithelium. Both experimental models of pulmonary edema and clinical studies are considered to demonstrate how active Na+ and active Cl- transport participate and regulate alveolar edema resolution. Some of the material in this chapter has been discussed in recent reviews. For decades, it was believed that Starling forces, i.e. differences in hydrostatic and protein osmotic pressures, accounted for removal of excess air space fluid. This misconception remained partly because experiments measuring solute fluxes across the lung epithelial and endothelial barriers were done at room temperature and the animal species used was the dog, a species that later was demonstrated to have a very low rate of active ion and fluid transport. Also, until the late 1970s and early 1980s, there were few good animal models to study the resolution of pulmonary edema. Furthermore, isolation and culture of alveolar epithelial type II cells was just evolving to become a useful experimental technique. Although removal of interstitial pulmonary edema by lung lymphatics and lung microcirculation had been discussed by Staub in his review of pulmonary edema, there was still no information on how pulmonary edema was removed from the distal air spaces of the mature lung.