Impact of antenatal inflammation on diaphragm muscle function in the preterm lamb

Abstract

The incidence of respiratory failure is higher in preterm babies than at any other time of life and clinically relevant antenatal exposures such as inflammation and sepsis may affect the development and function of the fetal diaphragm. We hypothesised that the preterm diaphragm is susceptible to phenotypic alteration induced by in utero exposure to inflammation.We used an established newborn sheep model of neonatal lung disease to determine the impact of in utero inflammatory exposure on the contractile function of the newborn diaphragm. Pregnant ewes received intra‐amniotic injections of saline or LPS (10 mg, E coli O55:B5; Sigma, Melb, Aust) at 2 d or 7 d prior to delivery. Ewes were sedated (IV Ketamine 10 mg/kg, Medetomidine 0.02 mg/kg) and received a spinal anaesthetic (2% Lignocaine, 3 mL) prior to the premature delivery of lambs at 121 d gestation (term = 150 d). At post‐mortem, the diaphragm was removed for assessment of contractile function.Acute in utero exposure to an inflammatory stimulus caused significant (~30%) weakness in the diaphragm muscle. Maximum specific forces from twitch and tetanic contractions were significantly lower after 2 d and 7 d exposure to LPS compared to saline controls. After 2 d LPS exposure, the twitch half‐relaxation time was significantly longer than both 7 d LPS and saline controls. There were no significant differences in the susceptibility to fatigue or to stretch‐induced muscle damage between the treatment groups.These data indicate that both short term (2 d) and longer term (7 d) in utero exposure to inflammation causes contractile dysfunction in the pre‐term diaphragm. This muscle weakness is likely to further impair the functional capacity of the diaphragm and limit the ability to cope with the increased mechanical loads associated with a structurally and functionally immature respiratory system.