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Original Research: CRITICAL CARE |

Preventive and Therapeutic Effects of Phosphoinositide 3-Kinase Inhibitors on Acute Lung InjuryPI3K Inhibitors in Acute Lung Injury

Chengshui Chen, MD, PhD; Xiaocong Fang, MD; Yaoli Wang, MD, PhD; Yuping Li, MD; Diane Wang; Xia Zhao, MD, PhD; Chunxue Bai, MD, PhD, FCCP; Xiangdong Wang, MD, PhD
Author and Funding Information

From the Department of Respiratory Medicine (Drs Chen and Li), The First Hospital, Wenzhou Medical College, Zhejiang, China; Department of Pulmonary Medicine (Drs Fang, Bai, and X. Wang and Ms D. Wang) and Biomedical Research Center (Dr X. Wang), Zhongshan Hospital, Fudan University, Shanghai, China; Intensive Care Unit (Dr Y. Wang), Daping Hospital, The Third Military Medical University, Chongqing, China; and Biomedical Center (Dr Zhao), Lund University, Lund, Sweden.

Correspondence to: Xiangdong Wang, MD, PhD, Department of Pulmonary Medicine, Biomedical Research Center, Zhongshan Hospital, Fudan University, 138 Yixueyuan Rd, 200032 Shanghai, China; e-mail: xiangdong.wang@telia.com


Drs Chen, Fang, and Y. Wang contributed equally to this article.

Funding/Support: The work was supported by a Key Project Grant from the Science & Technology Bureau of Zhejiang Province [2010C14011], an International Collaboration Project Grant from the Science & Technology Bureau of Wenzhou [H20100013], the Shanghai Leading Academic Discipline Project [Project Number B115], Fudan University [Distinguished Professor Grant], and the Shanghai Science & Technology Committee [08PJ1402900, 9540702600, 08DZ2293104].

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).


© 2011 American College of Chest Physicians


Chest. 2011;140(2):391-400. doi:10.1378/chest.10-3060
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Background:  Phosphoinositide 3-kinases (PI3Ks) are involved in a number of biologic responses. Recent preclinical studies demonstrated that the PI3K-dominant signal pathway could play an important role in the development of acute lung injury, although the mechanism remains unclear.

Methods:  CD-1 mice were administered different PI3K inhibitors either intranasally or intragastrically once a day for 3 days before intratracheal instillation of lipopolysaccharide at 4 h and 24 h. Effects of SHBM1009 on lipopolysaccharide-induced capillary permeability, leukocyte distribution and activation, and epithelial cell function were measured. Therapeutic effects of SHBM1009 on pancreatic elastase-induced lung injury were evaluated in rats.

Results:  The data demonstrated that the local delivery of PI3K inhibitors played more effective roles in the prevention of endotoxin-induced lung injury than the systemic delivery. The preventive effects of PI3K inhibitors varied most likely because of chemical properties, targeting sites, and pharmacokinetics. The local PI3K inhibitors prevented both endotoxin- and elastase-induced lung injury in mice and rats, possibly through directly inhibiting or inactivating the function of airway epithelial cells, which could not produce chemoattractant factors to activate neutrophils and macrophages.

Conclusions:  PI3K may be a therapeutic target for lung injury, and local delivery of PI3K inhibitors may be one of the optimal approaches for the therapy.

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