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CD4+CD25+Foxp3+ Tregs resolve experimental lung injury in mice and are present in humans with acute lung injury
Franco R. D’Alessio, … , John F. McDyer, Landon S. King
Franco R. D’Alessio, … , John F. McDyer, Landon S. King
Published September 21, 2009
Citation Information: J Clin Invest. 2009;119(10):2898-2913. https://doi.org/10.1172/JCI36498.
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Research Article

CD4+CD25+Foxp3+ Tregs resolve experimental lung injury in mice and are present in humans with acute lung injury

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Abstract

Acute lung injury (ALI) is characterized by rapid alveolar injury, inflammation, cytokine induction, and neutrophil accumulation. Although early events in the pathogenesis of ALI have been defined, the mechanisms underlying resolution are unknown. As a model of ALI, we administered intratracheal (i.t.) LPS to mice and observed peak lung injury 4 days after the challenge, with resolution by day 10. Numbers of alveolar lymphocytes increased as injury resolved. To examine the role of lymphocytes in this response, lymphocyte-deficient Rag-1–/– and C57BL/6 WT mice were exposed to i.t. LPS. The extent of injury was similar between the groups of mice through day 4, but recovery was markedly impaired in the Rag-1–/– mice. Adoptive transfer studies revealed that infusion of CD4+CD25+Foxp3+ Tregs as late as 24 hours after i.t. LPS normalized resolution in Rag-1–/– mice. Similarly, Treg depletion in WT mice delayed recovery. Treg transfer into i.t. LPS–exposed Rag-1–/– mice also corrected the elevated levels of alveolar proinflammatory cytokines and increased the diminished levels of alveolar TGF-β and neutrophil apoptosis. Mechanistically, Treg-mediated resolution of lung injury was abrogated by TGF-β inhibition. Moreover, BAL of patients with ALI revealed dynamic changes in CD3+CD4+CD25hiCD127loFoxp3+ cells. These results indicate that Tregs modify innate immune responses during resolution of lung injury and suggest potential targets for treating ALI, for which there are no specific therapies currently available.

Authors

Franco R. D’Alessio, Kenji Tsushima, Neil R. Aggarwal, Erin E. West, Matthew H. Willett, Martin F. Britos, Matthew R. Pipeling, Roy G. Brower, Rubin M. Tuder, John F. McDyer, Landon S. King

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Figure 3

AT of Tregs mediates resolution of lung injury in Rag-1–/– mice.

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AT of Tregs mediates resolution of lung injury in Rag-1–/– mice.
   
Rag...
Rag-1–/– mice were challenged with i.t. LPS and 1 hour afterward received PBS sham treatment or 1.0 × 106 WT CD4+CD25– or WT CD4+CD25+ splenocytes. (A) Rag-1–/– mouse survival over a 10-day period. †P < 0.05 versus sham control, log-rank test. (B) H&E stain of representative lung sections on day 10 after i.t. LPS and infusion of PBS or the indicated lymphocyte subsets. Original magnification, ×40. (C) Mean histopathological lung injury scores (n = 8–10 animals per group). *P < 0.05. (D and E) BAL total protein (D) and total cell counts (E) were determined in WT and Rag-1–/– mice on day 10 after AT (n = 10 per group). †P < 0.05 versus Rag-1–/– sham control. (F) Lung H&E staining demonstrate that AT of Tregs into injured Rag-1–/– mice as late as 24 hours after i.t. LPS achieved resolution of lung injury (n = 5 per group). Original magnification, ×40.

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