Delayed neonatal lung macrophage differentiation in a mouse model of in utero ethanol exposure

Abstract

We have previously demonstrated that fetal ethanol exposure deranges the function and viability of the neonatal alveolar macrophage. Although altered differentiation of the alveolar macrophage contributes to pulmonary disease states within the adult lung, the effects of fetal ethanol exposure on the normal differentiation of interstitial to alveolar macrophage in the newborn lung are unknown. In the current study, using a mouse model of fetal ethanol exposure, we hypothesized that altered terminal differentiation of the neonatal interstitial to alveolar macrophage contributes to the observed cellular dysfunction in the ethanol-exposed newborn mouse. Control alveolar macrophage differentiation was characterized by increased expression of CD32/CD11b (P < or = 0.05) and increased in vitro phagocytosis of Staphylococcus aureus (P < or = 0.05) compared with interstitial macrophage. After in utero ethanol exposure, both alveolar and interstitial macrophage lacked the acquisition of CD32/CD11b (P < or = 0.05) and displayed impaired in vitro phagocytosis (P < or = 0.05). Ethanol significantly increased transforming growth factor-beta(1) (TGF-beta(1)) in the bronchoalveolar lavage fluid (P < or = 0.05), as well as in both interstitial and alveolar macrophages (P < or = 0.05). Oxidant stress contributed to the ethanol-induced changes on the interstitial and alveolar cells, since maternal supplementation with the glutathione precursor S-adenosylmethionine during ethanol ingestion normalized CD32/CD11b (P < or = 0.05), phagocytosis (P < or = 0.05), and TGF-beta(1) in the bronchoalveolar lavage fluid and macrophages (P < or = 0.05). Contrary to our hypothesis, fetal ethanol exposure did not solely impair interstitial to alveolar macrophage differentiation. Rather, fetal ethanol exposure impaired both neonatal interstitial and alveolar macrophage phagocytic function and differentiation. Increased oxidant stress and elevated TGF-beta(1) contributed to the impaired differentiation of both interstitial and alveolar macrophage.

Maternal Alcohol Use During Pregnancy and Associated Morbidities in Very Low Birth Weight Newborns

“…Despite animal data suggesting that fetal alcohol exposure suppresses the immune response in the offspring, 7, 16, 29, 30 clinical evidence specifically evaluating alcohol’s effect on newborn immunity remains limited. Limited studies of children with fetal alcohol syndrome demonstrate increased rates of bacterial infections such as pneumonia.…”

The relative balance of GM-CSF and TGF-β1 regulates lung epithelial barrier function

“…For experimental measurements, HBE cells were seeded (5 ϫ 10 5 cells/well) on Transwell permeable supports. HBE cells treated with alcohol were incubated for 2 days in medium supplemented with 60 mM ethanol and maintained in a Billups-Rothenberg (Del Mar, CA) isolation chamber that was vapor equilibrated using ethanol-containing medium (16). Control cells were placed in an identical chamber without alcohol.…”

“…Transepithelial resistance (TER) was measured using an EVOM Ohmmeter (World Precision Instruments, Sarasota, FL), as previously described (9). For examining the effects of GM-CSF and TGF-␤ on HBE barrier function, cells were cultured for 4 days in DMEM ϩ 10% FBS, switched to DMEM ϩ 1% FBS for 2 days, and then incubated in serum-free DMEM for 16 For AECs, cells were cultured for 4 days in DMEM ϩ 10% FBS, switched to DMEM ϩ 1% FBS for 1 day, and then incubated with cytokines in DMEM ϩ 1% FBS for 16 h. In experiments using pharmacological agents or cytokines, agents were added to both the apical and basolateral media. Paracellular dye permeability was assessed by simultaneous measurement of the diffusion of two differentsized fluorescent dyes across the cell monolayer.…”

Nicotinic Acetylcholine Receptors Are Sensors For Ethanol In Lung Fibroblasts

“…Although the exact function(s) of nAChRs in lung remain unclear, several studies suggest important roles in lung development, inflammation, and cancer (Sekhon et al, 1999;Tournier and Birembaut, 2011). Interestingly, chronic ethanol exposure has been linked to the pathophysiology of these processes (Bagnardi et al, 2010;Gauthier et al, 2010a;Gauthier et al, 2010b;Lois et al, 1999;Tournier and Birembaut, 2011;Velasquez et al, 2002). It is intriguing to consider that nAChRs may serve as future potential targets for intervention to prevent the devastating effects of ethanol in lung and other tissues.…”