Abstract
Acute lung injury (ALI) causes significant morbidity and mortality. Fibroproliferation in ALI results in worse outcomes, but the mechanisms governing fibroproliferation remain poorly understood. Regulatory T cells (Tregs) are important in lung injury resolution. Their role in fibroproliferation is unknown. We sought to identify the role of Tregs in ALI fibroproliferation, using a murine model of lung injury. Wild-type (WT) and lymphocyte-deficient Rag-1-/- mice received intratracheal LPS. Fibroproliferationwascharacterizedby histology and the measurement of lung collagen. Lung fibrocytes were measured by flow cytometry. To dissect the role of Tregs in fibroproliferation, Rag-1-/- mice received CD4 +CD25+ (Tregs) or CD4+ CD25- Tcells (non-Tregs) at the time of LPS injury. To define the role of the chemokine (C-X-C motif) ligand 12 (CXCL12)-CXCR4 pathway in ALI fibroproliferation, Rag-1-/- mice were treated with the CXCR4 antagonist AMD3100 to block fibrocyte recruitment. WT and Rag-1-/- mice demonstrated significant collagen deposition on Day 3 after LPS. WT mice exhibited the clearance of collagen, but Rag-1-/- mice developed persistent fibrosis. This fibrosis was mediated by the sustained epithelial expression of CXCL12 (or stromal cell-derived factor 1 [SDF-1]) that led to increased fibrocyte recruitment. The adoptive transfer of Tregs resolved fibroproliferation by decreasing CXCL12 expression and subsequent fibrocyte recruitment. Blockade of the CXCL12-CXCR4 axis with AMD3100 also decreased lung fibrocytes and fibroproliferation. These results indicate a central role for Tregs in the resolution of ALI fibroproliferation by reducing fibrocyte recruitment along the CXCL12-CXCR4 axis. A dissection of the role of Tregs in ALI fibroproliferation may inform the design of new therapeutic tools for patients with ALI.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 35-43 |
| Number of pages | 9 |
| Journal | American Journal of Respiratory Cell and Molecular Biology |
| Volume | 48 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 2013 |
Fingerprint
Keywords
- Acute lung injury
- Fibrocytes
- Fibroproliferative ARDS
- Lung injury resolution
- Regulatory T cells
ASJC Scopus subject areas
- Cell Biology
- Pulmonary and Respiratory Medicine
- Molecular Biology
- Clinical Biochemistry
Cite this
Regulatory T cells reduce acute lung injury fibroproliferation by decreasing fibrocyte recruitment. / Garibaldi, Brian Thomas; D'Alessio, Franco; Mock, Jason R.; Files, D. Clark; Chau, Eric; Eto, Yoshiki; Drummond, M. Bradley; Aggarwal, Neil R.; Sidhaye, Venkataramana; King, Landon Stuart.
In: American Journal of Respiratory Cell and Molecular Biology, Vol. 48, No. 1, 01.2013, p. 35-43.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Regulatory T cells reduce acute lung injury fibroproliferation by decreasing fibrocyte recruitment
AU - Garibaldi, Brian Thomas
AU - D'Alessio, Franco
AU - Mock, Jason R.
AU - Files, D. Clark
AU - Chau, Eric
AU - Eto, Yoshiki
AU - Drummond, M. Bradley
AU - Aggarwal, Neil R.
AU - Sidhaye, Venkataramana
AU - King, Landon Stuart
PY - 2013/1
Y1 - 2013/1
N2 - Acute lung injury (ALI) causes significant morbidity and mortality. Fibroproliferation in ALI results in worse outcomes, but the mechanisms governing fibroproliferation remain poorly understood. Regulatory T cells (Tregs) are important in lung injury resolution. Their role in fibroproliferation is unknown. We sought to identify the role of Tregs in ALI fibroproliferation, using a murine model of lung injury. Wild-type (WT) and lymphocyte-deficient Rag-1-/- mice received intratracheal LPS. Fibroproliferationwascharacterizedby histology and the measurement of lung collagen. Lung fibrocytes were measured by flow cytometry. To dissect the role of Tregs in fibroproliferation, Rag-1-/- mice received CD4 +CD25+ (Tregs) or CD4+ CD25- Tcells (non-Tregs) at the time of LPS injury. To define the role of the chemokine (C-X-C motif) ligand 12 (CXCL12)-CXCR4 pathway in ALI fibroproliferation, Rag-1-/- mice were treated with the CXCR4 antagonist AMD3100 to block fibrocyte recruitment. WT and Rag-1-/- mice demonstrated significant collagen deposition on Day 3 after LPS. WT mice exhibited the clearance of collagen, but Rag-1-/- mice developed persistent fibrosis. This fibrosis was mediated by the sustained epithelial expression of CXCL12 (or stromal cell-derived factor 1 [SDF-1]) that led to increased fibrocyte recruitment. The adoptive transfer of Tregs resolved fibroproliferation by decreasing CXCL12 expression and subsequent fibrocyte recruitment. Blockade of the CXCL12-CXCR4 axis with AMD3100 also decreased lung fibrocytes and fibroproliferation. These results indicate a central role for Tregs in the resolution of ALI fibroproliferation by reducing fibrocyte recruitment along the CXCL12-CXCR4 axis. A dissection of the role of Tregs in ALI fibroproliferation may inform the design of new therapeutic tools for patients with ALI.
AB - Acute lung injury (ALI) causes significant morbidity and mortality. Fibroproliferation in ALI results in worse outcomes, but the mechanisms governing fibroproliferation remain poorly understood. Regulatory T cells (Tregs) are important in lung injury resolution. Their role in fibroproliferation is unknown. We sought to identify the role of Tregs in ALI fibroproliferation, using a murine model of lung injury. Wild-type (WT) and lymphocyte-deficient Rag-1-/- mice received intratracheal LPS. Fibroproliferationwascharacterizedby histology and the measurement of lung collagen. Lung fibrocytes were measured by flow cytometry. To dissect the role of Tregs in fibroproliferation, Rag-1-/- mice received CD4 +CD25+ (Tregs) or CD4+ CD25- Tcells (non-Tregs) at the time of LPS injury. To define the role of the chemokine (C-X-C motif) ligand 12 (CXCL12)-CXCR4 pathway in ALI fibroproliferation, Rag-1-/- mice were treated with the CXCR4 antagonist AMD3100 to block fibrocyte recruitment. WT and Rag-1-/- mice demonstrated significant collagen deposition on Day 3 after LPS. WT mice exhibited the clearance of collagen, but Rag-1-/- mice developed persistent fibrosis. This fibrosis was mediated by the sustained epithelial expression of CXCL12 (or stromal cell-derived factor 1 [SDF-1]) that led to increased fibrocyte recruitment. The adoptive transfer of Tregs resolved fibroproliferation by decreasing CXCL12 expression and subsequent fibrocyte recruitment. Blockade of the CXCL12-CXCR4 axis with AMD3100 also decreased lung fibrocytes and fibroproliferation. These results indicate a central role for Tregs in the resolution of ALI fibroproliferation by reducing fibrocyte recruitment along the CXCL12-CXCR4 axis. A dissection of the role of Tregs in ALI fibroproliferation may inform the design of new therapeutic tools for patients with ALI.
KW - Acute lung injury
KW - Fibrocytes
KW - Fibroproliferative ARDS
KW - Lung injury resolution
KW - Regulatory T cells
UR - http://www.scopus.com/inward/record.url?scp=84871902824&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84871902824&partnerID=8YFLogxK
U2 - 10.1165/rcmb.2012-0198OC
DO - 10.1165/rcmb.2012-0198OC
M3 - Article
C2 - 23002097
AN - SCOPUS:84871902824
VL - 48
SP - 35
EP - 43
JO - American Journal of Respiratory Cell and Molecular Biology
JF - American Journal of Respiratory Cell and Molecular Biology
SN - 1044-1549
IS - 1
ER -