Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis
Roderick J. Phillips, … , Michael P. Keane, Robert M. Strieter
Roderick J. Phillips, … , Michael P. Keane, Robert M. Strieter
Published August 1, 2004
Citation Information: J Clin Invest. 2004;114(3):438-446. https://doi.org/10.1172/JCI20997.
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Article Cell biology

Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis

Abstract

Previous reports have identified a circulating pool of CD45+ collagen I+ CXCR4+ (CD45+Col I+CXCR4+) cells, termed fibrocytes, that traffic to areas of fibrosis. No studies have demonstrated that these cells actually contribute to fibrosis, however. Pulmonary fibrosis was originally thought to be mediated solely by resident lung fibroblasts. Here we show that a population of human CD45+Col I+CXCR4+ circulating fibrocytes migrates in response to CXCL12 and traffics to the lungs in a murine model of bleomycin-induced pulmonary fibrosis. Next, we demonstrated that murine CD45+Col I+CXCR4+ fibrocytes also traffic to the lungs in response to a bleomycin challenge. Maximal intrapulmonary recruitment of CD45+Col I+CXCR4+ fibrocytes directly correlated with increased collagen deposition in the lungs. Treatment of bleomycin-exposed animals with specific neutralizing anti-CXCL12 Ab’s inhibited intrapulmonary recruitment of CD45+Col I+CXCR4+ circulating fibrocytes and attenuated lung fibrosis. Thus, our results demonstrate, we believe for the first time, that circulating fibrocytes contribute to the pathogenesis of pulmonary fibrosis.

Authors

Roderick J. Phillips, Marie D. Burdick, Kurt Hong, Marin A. Lutz, Lynne A. Murray, Ying Ying Xue, John A. Belperio, Michael P. Keane, Robert M. Strieter

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Intrapulmonary recruitment of CD45+Col I+CXCR4+ fibrocytes is greater th...
Intrapulmonary recruitment of CD45+Col I+CXCR4+ fibrocytes is greater than CD45+Col I+CCR7+ fibrocytes and correlates with collagen deposition in the lungs of bleomycin-exposed mice. (A and B) Single-cell suspensions were isolated from bleomycin- or saline-challenged lungs and blood buffy coats at the times indicated, triple-stained for CD45, Col I, and CXCR4 (A), or CD45, Col I, and CCR7 (lungs only) (B), and then examined by FACS analysis. n = 6 samples per group. BC, buffy coat. Data represent the mean ± SEM. *P < 0.05, significant differences between bleomycin and saline groups. **P < 0.05, significant differences between saline-exposed mice and the naive mice. (C) Mice were treated with either intratracheal bleomycin or saline for 8 days. Bone marrow was removed, triple-stained for CD45, Col I, and CXCR4, and then examined by FACS analysis. n = 3 samples per group. Data represent the mean ± SEM. *P < 0.05. (D) Kinetics of CXCL12 protein expression in lung tissue and plasma of mice exposed to either intratracheal bleomycin, saline, or naive control (day 0) as determined by ELISA. n = 6 samples in each group. Data represents the mean ± SEM. *P < 0.05, significant differences between bleomycin and saline groups. **P < 0.05, significant differences between saline-exposed mice and the naive mice.