Gestational age at time of in utero lipopolysaccharide exposure influences the severity of inflammation-induced diaphragm weakness in lambs

Kanakeswary Karisnan, Tanzila Mahzabin, Anthony J Bakker, Yong Song, Peter B Noble, J Jane Pillow, Gavin Jon Pinniger

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Abstract

The preterm diaphragm is functionally immature compared to its term counterpart. In utero inflammation further exacerbates preterm diaphragm dysfunction. We hypothesized that preterm lambs are more vulnerable to in utero inflammation induced diaphragm dysfunction compared with term lambs. Pregnant ewes received intra-amniotic (IA) injections of saline or 10mg lipopolysaccharide (LPS) 2d or 7d prior to delivery at 121d (preterm) or 145d (term) gestation. Diaphragm contractile function was assessed in vitro. Plasma cytokines and diaphragm myosin heavy chain (MHC) isoforms and oxidative stress were evaluated. Maximum diaphragm force in preterm control lambs was significantly lower (22%) than in term control lambs (p<0.001). Despite similar inflammatory cytokine responses to in utero LPS exposure, diaphragm function in preterm and term lambs was affected differentially. In term lambs, maximum force after a 2d LPS exposure was significantly lower than controls (by ~20%; p<0.05). In preterm lambs, maximum forces after 2d and 7d LPS exposures were significantly lower than controls (by ~30%; p<0.05). Peak twitch force after LPS exposure was significantly lower than controls in preterm, but not in term lambs. In term lambs, LPS exposure increased the proportion of MHC-I fibers, increased twitch contraction times and increased fatigue resistance relative to controls. In preterm diaphragm, the cross-sectional area of embryonic MHC fibers was significantly lower after 7d versus 2d LPS exposures. We conclude that preterm lambs are more vulnerable to IA LPS-induced diaphragm dysfunction than term lambs. In utero inflammation exacerbates diaphragm dysfunction and may increase susceptibility to postnatal respiratory failure.

Original languageEnglish
Pages (from-to)R523-R532
JournalAmerican Journal of Physiology - Regulatory Intergrative Compartive Physiology
Volume314
Issue number4
Early online date6 Dec 2017
DOIs
Publication statusPublished - Apr 2018

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Diaphragm
Gestational Age
Lipopolysaccharides
Inflammation
Myosin Heavy Chains
Cytokines
Respiratory Insufficiency
Fatigue
Protein Isoforms
Oxidative Stress
Pregnancy
Injections

Cite this

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title = "Gestational age at time of in utero lipopolysaccharide exposure influences the severity of inflammation-induced diaphragm weakness in lambs",
abstract = "The preterm diaphragm is functionally immature compared to its term counterpart. In utero inflammation further exacerbates preterm diaphragm dysfunction. We hypothesized that preterm lambs are more vulnerable to in utero inflammation induced diaphragm dysfunction compared with term lambs. Pregnant ewes received intra-amniotic (IA) injections of saline or 10mg lipopolysaccharide (LPS) 2d or 7d prior to delivery at 121d (preterm) or 145d (term) gestation. Diaphragm contractile function was assessed in vitro. Plasma cytokines and diaphragm myosin heavy chain (MHC) isoforms and oxidative stress were evaluated. Maximum diaphragm force in preterm control lambs was significantly lower (22{\%}) than in term control lambs (p<0.001). Despite similar inflammatory cytokine responses to in utero LPS exposure, diaphragm function in preterm and term lambs was affected differentially. In term lambs, maximum force after a 2d LPS exposure was significantly lower than controls (by ~20{\%}; p<0.05). In preterm lambs, maximum forces after 2d and 7d LPS exposures were significantly lower than controls (by ~30{\%}; p<0.05). Peak twitch force after LPS exposure was significantly lower than controls in preterm, but not in term lambs. In term lambs, LPS exposure increased the proportion of MHC-I fibers, increased twitch contraction times and increased fatigue resistance relative to controls. In preterm diaphragm, the cross-sectional area of embryonic MHC fibers was significantly lower after 7d versus 2d LPS exposures. We conclude that preterm lambs are more vulnerable to IA LPS-induced diaphragm dysfunction than term lambs. In utero inflammation exacerbates diaphragm dysfunction and may increase susceptibility to postnatal respiratory failure.",
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author = "Kanakeswary Karisnan and Tanzila Mahzabin and Bakker, {Anthony J} and Yong Song and Noble, {Peter B} and Pillow, {J Jane} and Pinniger, {Gavin Jon}",
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T1 - Gestational age at time of in utero lipopolysaccharide exposure influences the severity of inflammation-induced diaphragm weakness in lambs

AU - Karisnan, Kanakeswary

AU - Mahzabin, Tanzila

AU - Bakker, Anthony J

AU - Song, Yong

AU - Noble, Peter B

AU - Pillow, J Jane

AU - Pinniger, Gavin Jon

PY - 2018/4

Y1 - 2018/4

N2 - The preterm diaphragm is functionally immature compared to its term counterpart. In utero inflammation further exacerbates preterm diaphragm dysfunction. We hypothesized that preterm lambs are more vulnerable to in utero inflammation induced diaphragm dysfunction compared with term lambs. Pregnant ewes received intra-amniotic (IA) injections of saline or 10mg lipopolysaccharide (LPS) 2d or 7d prior to delivery at 121d (preterm) or 145d (term) gestation. Diaphragm contractile function was assessed in vitro. Plasma cytokines and diaphragm myosin heavy chain (MHC) isoforms and oxidative stress were evaluated. Maximum diaphragm force in preterm control lambs was significantly lower (22%) than in term control lambs (p<0.001). Despite similar inflammatory cytokine responses to in utero LPS exposure, diaphragm function in preterm and term lambs was affected differentially. In term lambs, maximum force after a 2d LPS exposure was significantly lower than controls (by ~20%; p<0.05). In preterm lambs, maximum forces after 2d and 7d LPS exposures were significantly lower than controls (by ~30%; p<0.05). Peak twitch force after LPS exposure was significantly lower than controls in preterm, but not in term lambs. In term lambs, LPS exposure increased the proportion of MHC-I fibers, increased twitch contraction times and increased fatigue resistance relative to controls. In preterm diaphragm, the cross-sectional area of embryonic MHC fibers was significantly lower after 7d versus 2d LPS exposures. We conclude that preterm lambs are more vulnerable to IA LPS-induced diaphragm dysfunction than term lambs. In utero inflammation exacerbates diaphragm dysfunction and may increase susceptibility to postnatal respiratory failure.

AB - The preterm diaphragm is functionally immature compared to its term counterpart. In utero inflammation further exacerbates preterm diaphragm dysfunction. We hypothesized that preterm lambs are more vulnerable to in utero inflammation induced diaphragm dysfunction compared with term lambs. Pregnant ewes received intra-amniotic (IA) injections of saline or 10mg lipopolysaccharide (LPS) 2d or 7d prior to delivery at 121d (preterm) or 145d (term) gestation. Diaphragm contractile function was assessed in vitro. Plasma cytokines and diaphragm myosin heavy chain (MHC) isoforms and oxidative stress were evaluated. Maximum diaphragm force in preterm control lambs was significantly lower (22%) than in term control lambs (p<0.001). Despite similar inflammatory cytokine responses to in utero LPS exposure, diaphragm function in preterm and term lambs was affected differentially. In term lambs, maximum force after a 2d LPS exposure was significantly lower than controls (by ~20%; p<0.05). In preterm lambs, maximum forces after 2d and 7d LPS exposures were significantly lower than controls (by ~30%; p<0.05). Peak twitch force after LPS exposure was significantly lower than controls in preterm, but not in term lambs. In term lambs, LPS exposure increased the proportion of MHC-I fibers, increased twitch contraction times and increased fatigue resistance relative to controls. In preterm diaphragm, the cross-sectional area of embryonic MHC fibers was significantly lower after 7d versus 2d LPS exposures. We conclude that preterm lambs are more vulnerable to IA LPS-induced diaphragm dysfunction than term lambs. In utero inflammation exacerbates diaphragm dysfunction and may increase susceptibility to postnatal respiratory failure.

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DO - 10.1152/ajpregu.00150.2017

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JF - American Journal of Physiology - Regulatory Intergrative Compartive Physiology

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