Abstract
Chorioamnionitis (inflammation of the fetal membranes) is strongly associated with preterm birth and in utero exposure to inflammation significantly impairs contractile function in the preterm lamb diaphragm. The fetal inflammatory response to intra-amniotic (IA) lipopolysaccharide (LPS) is orchestrated via interleukin 1 (IL-1). We aimed to determine if LPS induced contractile dysfunction in the preterm diaphragm is mediated via the IL-1 pathway. Pregnant ewes received IA injections of recombinant human IL-1 receptor antagonist (rhIL-1ra) (Anakinra; 100 mg) or saline (Sal) 3 h prior to second IA injections of LPS (4 mg) or Sal at 119d gestational age (GA). Preterm lambs were killed after delivery at 121d GA (term = 150 d). Muscle fibres dissected from the right hemi-diaphragm were mounted in an in vitro muscle test system for assessment of contractile function. The left hemi-diaphragm was snap frozen for molecular and biochemical analyses. Maximum specific force in lambs exposed to IA LPS (Sal/LPS group) was 25% lower than in control lambs (Sal/Sal group; p=0.025). LPS-induced diaphragm weakness was associated with higher plasma IL-6 protein, diaphragm IL-1β mRNA and oxidised glutathione levels. Pre-treatment with rhIL-1ra (rhIL-1ra/LPS) ameliorated the LPS-induced diaphragm weakness and blocked systemic and local inflammatory responses, but did not prevent the rise in oxidised glutathione. These findings indicate that LPS induced diaphragm dysfunction is mediated via IL-1 and occurs independently of oxidative stress. Therefore, the IL-1 pathway represents a potential therapeutic target in the management of impaired diaphragm function in preterm infants.
Highlights
A functioning diaphragm is critically important for the initiation and sustainment of spontaneous unsupported breathing
Maxwell et al reported that primate immature diaphragm has high proportion of immature muscle fibres that are highly oxidative and high mitochondrial content that may contribute to fatigue resistance [4]. These findings suggest that the relationship between MHC expression, contractile function and fatigability is less robust in fetal muscle compared to adult muscle
Chorioamnionitis is associated with increased interleukin 1 (IL-1) levels in the amniotic fluid and IL-1 is the major contributor to lung proinflammatory activity and injury
Summary
A functioning diaphragm is critically important for the initiation and sustainment of spontaneous unsupported breathing. Like the lung, the preterm diaphragm is structurally and functionally immature at birth and is poorly equipped to meet the mechanical demands of breathing. Inadequate diaphragm development may enhance the vulnerability to PLOS ONE | DOI:10.1371/journal.pone.0124390. IL-1 Mediates LPS Induced Diaphragm Weakness additional in utero exposures that are strongly associated with very preterm births such as chorioamnionitis. IL-1 has a critical role in the inflammatory pathway associated with pulmonary responses to chorioamnionitis [1]. Identification of a similar pathway as a determinant of an adverse impact of antenatal inflammation on diaphragm function would support treatment strategies targeting inhibition of the IL-1 pathway
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