Editors' ChoiceLung Immunology

Regulation Ain’t So Bad: Tregs in Acute Lung Injury

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Science Translational Medicine  03 Oct 2012:
Vol. 4, Issue 154, pp. 154ec180
DOI: 10.1126/scitranslmed.3005015

“When you can’t breathe, nothing else matters” (American Lung Association). Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), have many causes; however, there are likely some fundamental and shared molecular and physiological mechanisms that underlie ALI/ARDS pathology. Patients with ALI/ARDS have a mortality rate of 40 to 44%, making research into ALI disease mechanisms a high priority.

ARDS develops in stages, beginning with the collection of excess fluid and inflammatory cells in the lung. This exudative stage is followed by a fibroproliferative phase, which is characterized by alveolar fibroblast accumulation and extensive collagen deposition/remodeling. The fibroproliferative phase is associated with higher mortality, but the mechanisms that mediate resolution of fibroproliferation remain largely unknown. Because regulatory T cells (Tregs) contribute to resolving lung inflammation, the authors wanted to know whether Tregs mitigated fibroproliferation in susceptible lungs.

Using an ALI model of intratracheal lipopolysaccharide instillation in mice, Garibaldi et al. show that lymphocyte-deficient mice have persistent fibroproliferative responses, with sustained fibrocyte recruitment to their lungs, and reduced survival. However, adoptive transfer of Tregs (CD4+CD25+ T cells) into these lymphocyte-deficient mice reduced lung inflammation and fibrocyte influx and resolved lung fibroproliferation. The authors further showed that Tregs reduced fibrocyte influx by decreasing lung CXCL12, a chemokine that promotes fibrocyte trafficking into lungs. Additional experiments that blocked CXCR4, the receptor for CXCL12, also decreased lung inflammation, injury, fibroproliferation, and fibrocyte recruitment.

This work is particularly important because once patients head into the latter fibroproliferative stage of ALI/ARDS, irreversible lung fibrosis becomes established, with severe clinical consequences. Translating these findings to human disease would be novel, focusing on (i) enhancing Treg cell function and (ii) the resolution of inflammation and fibroproliferation and ultimately the prevention of post-ALI/ARDS lung fibrosis. Evaluating the role and mechanisms of Tregs in human ALI will be a crucial next chapter in this important line of inquiry. As for those unfortunate few who have to live with the fibrotic sequelae of ALI/ARDS, we are humbly reminded that “When you can’t breathe, nothing else [truly] matters.”

B. T. Garibaldi et al., Regulatory T cells reduce acute lung injury fibroproliferation by decreasing fibrocyte recruitment. Am. J. Respir. Cell Mol. Biol., 20 September 2012 (10.1165/rcmb.2012-0198OC) [PubMed]

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