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Shock. 2013 Oct;40(4):312-9. doi: 10.1097/SHK.0b013e3182a102e5.

Inhibition of notch signaling protects mouse lung against zymosan-induced injury.

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  • 1*Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province; and †Department of Anesthesiology, General Hospital of Chengdu Military Region, Chengdu, Sichuan Province, People's Republic of China; ‡Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, West Virginia; §Graduate Institute of Biotechnology, Chinese Culture University, Yang-Ming-Shan, Taipei, Taiwan, Republic of China; and ∥Department of Pathology and Pathophysiology, Fourth Military Medical University, and ¶Surgical ICU, Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi Province, People's Republic of China.

Abstract

Notch signaling, a critical pathway in cell fate determination, is well known to be involved in immune and inflammatory reactions, whereas its role in acute lung injury (ALI) remains unclear. Here, we report that notch signal activity is upregulated in lung tissue harvested from an ALI mouse model (induced by zymosan). We showed that notch signal activity in lung tissue was increased 6 h after zymosan injection and peaked at 24 h. Inhibition of notch signaling by either pre- or post-zymosan treatment with N-[N-(3,5-difluorophenacetyl)-l-alanyl]-(S)-phenylglycine t-butyl ester (DAPT) significantly reduced lung injury, characterized by improvement in lung histopathology, lung permeability (protein concentration in bronchoalveolar lavage fluid and lung wet-to-dry weight ratio), lung inflammation (bronchoalveolar lavage fluid cell count, lung myeloperoxidase, and tumor necrosis factor α), and also alleviated systemic inflammation and tissue damage, thus increasing the 7-day survival rate in zymosan-challenged mice. In conclusion, the role of notch signaling is functionally significant in the development of ALI. Inhibition of notch signaling by pretreatment or posttreatment with DAPT likely exerts its effects in part by mediating the expression of proinflammatory and anti-inflammatory cytokines and influencing tissue neutrophil recruitment. These results also imply that notch inhibitors may help attenuate local inflammatory lung damage.

[PubMed - indexed for MEDLINE]
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