TY - JOUR
T1 - Pulmonary epithelial TLR4 activation leads to lung injury in neonatal necrotizing enterocolitis
AU - Jia, Hongpeng
AU - Sodhi, Chhinder P.
AU - Yamaguchi, Yukihiro
AU - Lu, Peng
AU - Martin, Laura Y.
AU - Good, Misty
AU - Zhou, Qinjie
AU - Sung, Jungeun
AU - Fulton, William B.
AU - Nino, Diego F.
AU - Prindle, Thomas
AU - Ozolek, John A.
AU - Hackam, David J.
N1 - Funding Information:
D.J.H. is supported by National Institutes of Health Grants R01GM078238 and R01DK083752.
Publisher Copyright:
Copyright © 2016 by The American Association of Immunologists, Inc.
PY - 2016/8/1
Y1 - 2016/8/1
N2 - We seek to define the mechanisms leading to the development of lung disease in the setting of neonatal necrotizing enterocolitis (NEC), a life-threatening gastrointestinal disease of premature infants characterized by the sudden onset of intestinal necrosis. NEC development in mice requires activation of the LPS receptor TLR4 on the intestinal epithelium, through its effects on modulating epithelial injury and repair. Although NEC-associated lung injury is more severe than the lung injury that occurs in premature infants without NEC, the mechanisms leading to its development remain unknown. In this study, we now show that TLR4 expression in the lung gradually increases during postnatal development, and that mice and humans with NEC-associated lung inflammation express higher levels of pulmonary TLR4 than do age-matched controls. NEC in wild-type newborn mice resulted in significant pulmonary injury that was prevented by deletion of TLR4 from the pulmonary epithelium, indicating a role for pulmonary TLR4 in lung injury development. Mechanistically, intestinal epithelial TLR4 activation induced high-mobility group box 1 release from the intestine, which activated pulmonary epithelial TLR4, leading to the induction of the neutrophil recruiting CXCL5 and the influx of proinflammatory neutrophils to the lung. Strikingly, the aerosolized administration of a novel carbohydrate TLR4 inhibitor prevented CXCL5 upregulation and blocked NEC-induced lung injury in mice. These findings illustrate the critical role of pulmonary TLR4 in the development of NEC-associated lung injury, and they suggest that inhibition of this innate immune receptor in the neonatal lung may prevent this devastating complication of NEC.
AB - We seek to define the mechanisms leading to the development of lung disease in the setting of neonatal necrotizing enterocolitis (NEC), a life-threatening gastrointestinal disease of premature infants characterized by the sudden onset of intestinal necrosis. NEC development in mice requires activation of the LPS receptor TLR4 on the intestinal epithelium, through its effects on modulating epithelial injury and repair. Although NEC-associated lung injury is more severe than the lung injury that occurs in premature infants without NEC, the mechanisms leading to its development remain unknown. In this study, we now show that TLR4 expression in the lung gradually increases during postnatal development, and that mice and humans with NEC-associated lung inflammation express higher levels of pulmonary TLR4 than do age-matched controls. NEC in wild-type newborn mice resulted in significant pulmonary injury that was prevented by deletion of TLR4 from the pulmonary epithelium, indicating a role for pulmonary TLR4 in lung injury development. Mechanistically, intestinal epithelial TLR4 activation induced high-mobility group box 1 release from the intestine, which activated pulmonary epithelial TLR4, leading to the induction of the neutrophil recruiting CXCL5 and the influx of proinflammatory neutrophils to the lung. Strikingly, the aerosolized administration of a novel carbohydrate TLR4 inhibitor prevented CXCL5 upregulation and blocked NEC-induced lung injury in mice. These findings illustrate the critical role of pulmonary TLR4 in the development of NEC-associated lung injury, and they suggest that inhibition of this innate immune receptor in the neonatal lung may prevent this devastating complication of NEC.
UR - http://www.scopus.com/inward/record.url?scp=84979534578&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.1600618
DO - 10.4049/jimmunol.1600618
M3 - Article
C2 - 27307558
AN - SCOPUS:84979534578
VL - 197
SP - 859
EP - 871
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 3
ER -