School of Human Sciences, The University of Western Australia, Crawley, Western Australia, Australia.
Neonatal Cardiorespiratory Health, Neonatal Research, Telethon Kids Institute, Nedlands, Western Australia, Australia.
J Appl Physiol (1985). 2022 Oct 1;133(4):959-969. doi: 10.1152/japplphysiol.00097.2022. Epub 2022 Sep 8.
Abnormalities of the airway smooth muscle (ASM) layer in asthma may develop before birth. We hypothesize that antenatal inflammation causes physiological abnormalities of the ASM that predisposes asthma. This study determined the short-term effects of antenatal inflammation on the developing ASM. Fourteen pregnant ewes were randomly assigned to one of three groups. Fetal lambs were exposed to intra-amniotic injections of lipopolysaccharide (LPS, = 4) or saline (controls; = 5) at 127 days' gestational age (GA). Preterm lambs were surgically delivered at 129 days' GA and received intensive care for 7 days before euthanasia. Naïve fetal controls ( = 5) were delivered and euthanized at 136 days' GA. ASM force to acetylcholine was measured in bronchial rings and normalized to ring length (tension) and ASM cross-sectional area (stress). Airway narrowing (% volume) to acetylcholine was assessed in bronchial segments. Fetal controls were structurally and functionally similar to saline-exposed lambs. Compared with saline, LPS-exposed lambs had increased macrophages in lung tissue ( = 0.0002) and interleukin-8 in alveolar wash ( = 0.003). LPS exposure increased ASM thickness ( = 0.005), airway narrowing ( = 0.003), ASM tension ( = 0.0002), and contractile stress ( < 0.0001). Notably, LPS-exposed lambs were more dependent on mechanical ventilation, and both LPS ( < 0.001) and ventilation ( = 0.012) were independent factors in increasing ASM stress. Only LPS independently increased ASM thickness ( = 0.045). Results indicate that antenatal exposure to LPS and subsequent mechanical ventilation promotes intrinsic changes to the ASM that enhances bronchoconstriction. If persistent into postnatal life, these developmental abnormalities may contribute to the known association between chorioamnionitis and asthma. Abnormalities of the airway smooth muscle (ASM) layer in asthma may develop before birth. Using an ovine model of antenatal inflammation, we demonstrate thickening and increased contraction of the premature ASM layer. If such physiological abnormalities persist throughout postnatal life, this represents a predisposition to an asthma diagnosis.
哮喘患者的气道平滑肌（ASM）层异常可能在出生前就已经发生。我们假设产前炎症导致 ASM 的生理异常，从而使哮喘易患。本研究旨在确定产前炎症对发育中的 ASM 的短期影响。将 14 只怀孕母羊随机分为三组。胎羊在 127 天的胎龄（GA）时接受羊膜内注射脂多糖（LPS，n=4）或生理盐水（对照，n=5）。早产羔羊在 129 天 GA 时接受剖宫产，并接受 7 天的重症监护，然后安乐死。5 只新生胎羊作为对照，在 136 天 GA 时剖宫产并安乐死。通过测量支气管环对乙酰胆碱的收缩力并将其归一化为环长度（张力）和 ASM 横截面积（应力）来评估 ASM 对乙酰胆碱的收缩反应。通过评估支气管段对乙酰胆碱的气道狭窄（%体积）来评估气道狭窄。与生理盐水暴露的羔羊相比，LPS 暴露的羔羊肺组织中的巨噬细胞（p=0.0002）和肺泡灌洗液中的白细胞介素-8（IL-8）（p=0.003）增加。LPS 暴露增加了 ASM 厚度（p=0.005）、气道狭窄（p=0.003）、ASM 张力（p=0.0002）和收缩应力（p＜0.0001）。值得注意的是，LPS 暴露的羔羊更依赖于机械通气，LPS（p＜0.001）和通气（p=0.012）都是增加 ASM 应力的独立因素。只有 LPS 独立地增加了 ASM 厚度（p=0.045）。结果表明，产前接触 LPS 和随后的机械通气促进了 ASM 的内在变化，从而增强了支气管收缩。如果这种发育异常持续到出生后，可能与已知的绒毛膜羊膜炎和哮喘之间的关联有关。哮喘患者的气道平滑肌（ASM）层异常可能在出生前就已经发生。使用产前炎症的绵羊模型，我们发现早产 ASM 层变厚和收缩增加。如果这种生理异常在整个出生后持续存在，这可能会增加哮喘的诊断倾向。
