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      Pulmonary Epithelial TLR4 Activation Leads to Lung Injury in Neonatal Necrotizing Enterocolitis.

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          Abstract

          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.

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          Author and article information

          Journal
          J. Immunol.
          Journal of immunology (Baltimore, Md. : 1950)
          The American Association of Immunologists
          1550-6606
          0022-1767
          Aug 01 2016
          : 197
          : 3
          Affiliations
          [1 ] Division of General Pediatric Surgery, Johns Hopkins University and Bloomberg Children's Center, Johns Hopkins Hospital, Baltimore, MD 21287;
          [2 ] Division of Newborn Medicine, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, Pittsburgh, PA 15224; and.
          [3 ] Division of Pediatric Pathology, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, Pittsburgh, PA 15224.
          [4 ] Division of General Pediatric Surgery, Johns Hopkins University and Bloomberg Children's Center, Johns Hopkins Hospital, Baltimore, MD 21287; Dhackam1@jhmi.edu.
          Article
          jimmunol.1600618 NIHMS791546
          10.4049/jimmunol.1600618
          4955761
          27307558

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