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

Publication ,  Journal Article
D'Alessio, FR; Tsushima, K; Aggarwal, NR; West, EE; Willett, MH; Britos, MF; Pipeling, MR; Brower, RG; Tuder, RM; McDyer, JF; King, LS
Published in: J Clin Invest
October 2009

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-beta and neutrophil apoptosis. Mechanistically, Treg-mediated resolution of lung injury was abrogated by TGF-beta 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.

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Published In

J Clin Invest

DOI

EISSN

1558-8238

Publication Date

October 2009

Volume

119

Issue

10

Start / End Page

2898 / 2913

Location

United States

Related Subject Headings

  • T-Lymphocytes, Regulatory
  • T-Lymphocyte Subsets
  • Survival Rate
  • Neutrophils
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Macrophages, Peritoneal
  • Lung
 

Citation

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D’Alessio, F. R., Tsushima, K., Aggarwal, N. R., West, E. E., Willett, M. H., Britos, M. F., … King, L. S. (2009). CD4+CD25+Foxp3+ Tregs resolve experimental lung injury in mice and are present in humans with acute lung injury. J Clin Invest, 119(10), 2898–2913. https://doi.org/10.1172/JCI36498
D’Alessio, Franco R., Kenji Tsushima, Neil R. Aggarwal, Erin E. West, Matthew H. Willett, Martin F. Britos, Matthew R. Pipeling, et al. “CD4+CD25+Foxp3+ Tregs resolve experimental lung injury in mice and are present in humans with acute lung injury.J Clin Invest 119, no. 10 (October 2009): 2898–2913. https://doi.org/10.1172/JCI36498.
D’Alessio FR, Tsushima K, Aggarwal NR, West EE, Willett MH, Britos MF, et al. CD4+CD25+Foxp3+ Tregs resolve experimental lung injury in mice and are present in humans with acute lung injury. J Clin Invest. 2009 Oct;119(10):2898–913.
D’Alessio, Franco R., et al. “CD4+CD25+Foxp3+ Tregs resolve experimental lung injury in mice and are present in humans with acute lung injury.J Clin Invest, vol. 119, no. 10, Oct. 2009, pp. 2898–913. Pubmed, doi:10.1172/JCI36498.
D’Alessio FR, Tsushima K, Aggarwal NR, West EE, Willett MH, Britos MF, Pipeling MR, Brower RG, Tuder RM, McDyer JF, King LS. CD4+CD25+Foxp3+ Tregs resolve experimental lung injury in mice and are present in humans with acute lung injury. J Clin Invest. 2009 Oct;119(10):2898–2913.

Published In

J Clin Invest

DOI

EISSN

1558-8238

Publication Date

October 2009

Volume

119

Issue

10

Start / End Page

2898 / 2913

Location

United States

Related Subject Headings

  • T-Lymphocytes, Regulatory
  • T-Lymphocyte Subsets
  • Survival Rate
  • Neutrophils
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Macrophages, Peritoneal
  • Lung