The International Journal of Biochemistry & Cell Biology 40 (2008) 2129–2140
Available online at www.sciencedirect.com
Fibrocytes are a potential source of lung fibroblasts
in idiopathic pulmonary fibrosis
Annika Andersson-Sj¨ oland
a,1
, Carolina Garc´ ıa de Alba
b,1
,
Kristian Nihlberg
c
, Carina Becerril
b
, Remedios Ram´ ırez
d
, Annie Pardo
d
,
Gunilla Westergren-Thorsson
a,c
, Mois´ es Selman
b,∗
a
Department of Clinical Medical Science, Division of Respiratory Medicine and Allergology, Lund University, Sweden
b
Instituto Nacional de Enfermedades Respiratorias, Tlalpan 4502, CP 14080, M´ exico, D.F., Mexico
c
Department of Experimental Medical Science, Unit of Lung Biology, Lund University, Sweden
d
Facultad de Ciencias, Universidad Nacional Aut´ onoma de M´ exico, Mexico
Received 3 November 2007; received in revised form 12 February 2008; accepted 13 February 2008
Available online 11 March 2008
Abstract
Idiopathic pulmonary fibrosis is characterized by the accumulation of fibroblasts/myofibroblasts and aberrant remodeling of
the lung parenchyma. However, the sources of fibroblasts in IPF lungs are unclear. Fibrocytes are circulating progenitors of
fibroblasts implicated in wound healing and fibrosis. In this study we evaluated evidence for the presence of fibrocytes in the
lung of patients with idiopathic pulmonary fibrosis by immunofluorescence and confocal microscopy. Fibrocytes were identified
in tissues in 8 out of 9 fibrotic lungs. Combinations including CXCR4 and a mesenchymal marker stained significantly more
fibrocytes/mm
2
of tissue compared with combinations using CD34 or CD45RO with mesenchymal markers: CXCR4/procollagen-I
(10.3 ± 2.9 fibrocytes/mm
2
) and CXCR4/prolyl-4-hydroxylase (4.1 ± 3.1), versus CD34/procollagen-I (2.8 ± 3.0), CD34/SMA
(2.2 ± 1.6) and CD45RO/prolyl-4-hydroxylase (1.3 ± 1.6); p < 0.003. There was a positive correlation between the abundance of
fibroblastic foci and the amount of lung fibrocytes (r = 0.79; p < 0.02). No fibrocytes were identified in normal lungs. The fibrocyte
attractant chemokine CXCL12 increased in plasma [median: 2707.5 pg/ml (648.1–4884.7) versus 1751.5 pg/ml (192.9–2686.0) from
healthy controls; p < 0.003)] and was detectable in the bronchoalveolar lavage fluid of 40% of the patients but not in controls. In the
lung CXCL12 was strongly expressed by alveolar epithelial cells. A negative correlation between plasma levels of CXCL12 with
lung diffusing capacity for carbon monoxide (DLCO) (r = -0.56; p < 0.03) and oxygen saturation on exercise was found (r = -0.41;
p < 0.04). These findings indicate that circulating fibrocytes, likely recruited through the CXCR4/CXCL12 axis, may contribute to
the expansion of the fibroblast/myofibroblast population in idiopathic pulmonary fibrosis.
© 2008 Elsevier Ltd. All rights reserved.
Keywords: Pulmonary fibrosis; Fibrocytes; Fibroblasts; CXCL12; Fibroblastic foci
∗
Corresponding author. Fax: +52 55 5665 4623.
E-mail address: mselmanl@yahoo.com.mx (M. Selman).
1
These authors contributed equally to this study.
1. Introduction
Idiopathic pulmonary fibrosis (IPF) is a chronic, pro-
gressive, and usually lethal lung disease of unknown
etiology (Gross & Hunninghake, 2001). Expansion of
the fibroblast/myofibroblast population with the forma-
tion of fibroblastic foci in the lung is a characteristic of
1357-2725/$ – see front matter © 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.biocel.2008.02.012