Intrauterine growth restriction predisposes to airway inflammation without disruption of epithelial integrity in postnatal male mice

Abstract

Evidence from animal models demonstrate that intrauterine growth restriction (IUGR) alters airway structure and function which may affect susceptibility to disease. Airway inflammation and dysregulated epithelial barrier properties are features of asthma which have not been examined in the context of IUGR. This study used a maternal hypoxia-induced IUGR mouse model to assess lung-specific and systemic inflammation and airway epithelial tight junctions (TJs) protein expression. Pregnant BALB/c mice were housed under hypoxic conditions (10.5% O2) from gestational day (GD) 11 to 17.5 (IUGR group; term, GD 21). Following hypoxic exposure, mice were returned to a normoxic environment (21% O2). A Control group was housed under normoxic conditions throughout pregnancy. Offspring weights were recorded at 2 and 8 weeks of age and euthanized for bronchoalveolar lavage (BAL) and peritoneal cavity fluid collection for inflammatory cells counts. From a separate group of mice, right lungs were collected for Western blotting of TJs proteins. IUGR offspring had greater inflammatory cells in the BAL fluid but not in peritoneal fluid compared with Controls. At 8 weeks of age, interleukin (IL)-2, IL-13, and eotaxin concentrations were higher in male IUGR compared with male Control offspring but not in females. IUGR had no effect on TJs protein expression. Maternal hypoxia-induced IUGR increases inflammatory cells in the BAL fluid of IUGR offspring with no difference in TJs protein expression. Increased cytokine release, specific to the lungs of IUGR male offspring, indicates that both IUGR and sex can influence susceptibility to airway disease.

Intrauterine Growth Restriction Promotes Postnatal Airway Hyperresponsiveness Independent of Allergic Disease

“…The animal model of IUGR used in this study is robust; the reduction in body weight (at birth and 8 weeks of age) is comparable to that observed previously (8)(9)(10)(11)(12), affecting both male and female offspring (10,11). An acute allergy exposure protocol was preferred as this produces an inflammatorymediated increase in airway responsiveness (13,22), without altering body weight (13,23).…”

“…Functional changes after IUGR were not associated with airway remodeling (8,9), rather our data implicated a shift in inflammatory phenotype; an increase in macrophages in the bronchial alveolar lavage (BAL) fluid from both male and female offspring with males also demonstrating an increase in interleukin (IL)-2, IL-13, and eotaxin (10). Importantly, this shift in inflammatory phenotype was the result of a prenatal disruption that persisted into adult life and occurred without exposure to typical environmental triggers (10). Together these observations suggest that developmental changes in airway responsiveness that occur concomitantly with inflammation will alter the susceptibility to environmental influences and subsequent airway disease.…”

“…After establishing a mouse model of hypoxiainduced IUGR, we demonstrated airway hyperresponsiveness in female offspring and hyporesponsiveness in males (8). Functional changes after IUGR were not associated with airway remodeling (8,9), rather our data implicated a shift in inflammatory phenotype; an increase in macrophages in the bronchial alveolar lavage (BAL) fluid from both male and female offspring with males also demonstrating an increase in interleukin (IL)-2, IL-13, and eotaxin (10). Importantly, this shift in inflammatory phenotype was the result of a prenatal disruption that persisted into adult life and occurred without exposure to typical environmental triggers (10).…”

“…Allergy is a major risk factor for asthma (21) and may differentially impact individuals that were growthrestricted in utero. The present study used an established mouse model of maternal hypoxia-induced IUGR (8)(9)(10)(11)(12) to examine changes in airway responsiveness in IUGR offspring that were subsequently sensitized and challenged with an allergic stimulus i.e., OVA. Findings were unexpected in that the independent effects of IUGR and allergy in promoting AHR did not enhance bronchoconstriction when both abnormalities were combined.…”

“…Thirty pregnant BALB/c mice (gestational day "GD" 7) were obtained from the Animal Resources Center (Murdoch, WA, Australia). Mice were exposed to 10.5% O 2 from GD 11 to GD 17.5 (hypoxic conditions; IUGR group) (8)(9)(10)(11)(12) which corresponds to the pseudoglandular-canalicular stage in fetal mouse lung development, and therefore peak airway development. At GD 17.5, the pregnant mice were removed from the hypoxic chamber and returned to normoxic conditions (21% O 2 ) for the remainder of the pregnancy.…”