Content uploaded by Robert M Strieter
Author content
All content in this area was uploaded by Robert M Strieter on Dec 15, 2013
Content may be subject to copyright.
Review series
The Journal of Clinical Investigation http://www.jci.org Volume 117 Number 3 March 2007 549
The role of CXC chemokines in pulmonary fibrosis
Robert M. Strieter,1 Brigitte N. Gomperts,2 and Michael P. Keane3
1Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
2Division of Pediatric Hematology/Oncology, Department of Pediatrics, and 3Division of Pulmonary, Critical Care Medicine, and Hospitalists,
David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
The CXC chemokine family is a pleiotropic family of cytokines that are involved in promoting the trafficking of
various leukocytes, in regulating angiogenesis and vascular remodeling, and in promoting the mobilization and
trafficking of mesenchymal progenitor cells such as fibrocytes. These functions of CXC chemokines are important
in the pathogenesis of pulmonary fibrosis and other fibroproliferative disorders. In this Review, we discuss the biol-
ogy of CXC chemokine family members, specifically as it relates to their role in regulating vascular remodeling and
trafficking of circulating mesenchymal progenitor cells (also known as fibrocytes) in pulmonary fibrosis.
Introduction
The body’s response to various known and unknown (idiopathic)
processes in the lung can lead to pulmonary fibrosis. The most
common and devastating form of pulmonary fibrosis is referred
to as idiopathic pulmonary fibrosis (IPF). IPF is a chronic, and
usually fatal, pulmonary disorder with a mortality rate of approxi-
mately 70% five years after diagnosis (1, 2). Most reported cases of
IPF seem to be spontaneous, with less than 2% of cases familial in
character (3, 4). The prevalence of IPF increases with age (2, 5). The
term IPF was previously applied to all cases of pulmonary fibro-
sis that did not have a recognized cause. However, it is currently
reserved for, and is synonymous with, the pathological diagnosis
of usual interstitial pneumonia (UIP) following lung biopsy. The
hallmark of UIP is temporal heterogeneity (that is, areas of estab-
lished fibrosis interspersed with areas of relatively normal lung,
and gradations between these two extremes) and architectural loss
and chronic scarring accompanied by microscopic honeycomb-
like structural change in the subvisceral pleura region (Figure 1).
The fibrosis is present in the interstitial space (the space between
the endothelium and the basement membrane, beneath the epi-
thelium), which includes the alveolar walls. Other distinguish-
ing features of UIP include the relative paucity of inflammation,
a hyperplastic epithelium, and the presence of focal collections
of fibroblasts, referred to as fibroblastic foci. This has led some
investigators to hypothesize that IPF is a disease that is character-
ized by repetitive epithelial injury and abnormal repair (6). The
absence of marked inflammatory infiltrates has led to substantial
controversy as to the role of inflammation in IPF. This absence of
inflammation does not, however, exclude a role for inflammation
in the initiation of the injury that subsequently leads to fibrosis
(7, 8). Furthermore, the origin and importance of the fibroblastic
foci is controversial. It has recently been suggested that they are
not discrete foci but in fact represent an organized reticulum that
courses through the lung (9). Interestingly, this reticulum is sur-
rounded by an extensive capillary network, which suggests that
vascular remodeling is an important component of pulmonary
fibrosis (9). The pathological findings regarding UIP contrast with
those regarding cryptogenic organizing pneumonia (COP), which
is characterized by airway aggregates of fibroblasts in an imma-
ture collagen matrix. The lung architecture is typically preserved in
COP, and although there might be interstitial inflammation, there
is no interstitial fibrosis. COP typically has an excellent prognosis
and does not lead to end-stage fibrosis. Why then do these two pat-
terns of lung injury, each with a substantial presence of fibroblasts
and collagen matrices and variable degrees of vascular remodeling,
have two different outcomes? It is probable that the preservation
of the lung architecture and the intact basement membrane allows
repair to proceed normally in COP, as opposed to the aberrant
repair that is seen in UIP.
One of the major limitations to pulmonary fibrosis research is
the lack of a good animal model of fibrotic lung disease, particu-
larly a model of IPF. Bleomycin has been used in mice to initiate
fibrotic lung lesions that have many of the histological compo-
nents of IPF (10, 11). Bleomycin administration results in epitheli-
al cell necrosis within 24 hours, acute alveolitis 2–3 days following
challenge, and intense interstitial inflammation 4–12 days follow-
ing challenge (10, 11). Fibroblast proliferation and ECM synthe-
sis are initiated 4–14 days after challenge, with collagen content
elevated approximately 2-fold 3 weeks following challenge (10,
11). Furthermore, the injury is self limited and begins to resolve
after 4–6 weeks. Although these pathologic changes clearly occur
in a more rapid fashion than in human IPF, and not withstanding
the fact that the injury is self limited and spontaneously resolves
with time, the bleomycin model has been widely used as a model
of human pulmonary fibrosis and can provide useful insights into
the biology of lung injury, fibrosis, and repair.
In this Review, we focus on the role of CXC chemokines in
regulating vascular remodeling and extravasation of circulating
mesenchymal progenitor cells (also known as fibrocytes) in pul-
monary fibrosis. We present data from animal models of fibrosis,
particularly the bleomycin model of pulmonary fibrosis, which
provide a conceptual framework from which to begin to address
the pathogenesis of the human disease IPF.
Angiogenesis: vascular remodeling relevant to
pulmonary fibrosis
Angiogenesis is defined as the growth of new blood vessels and is
a critical biological event that occurs during various physiologic
and pathologic processes (12). Pathological angiogenesis is associ-
ated with all chronic inflammatory and chronic fibroproliferative
disorders as well as with tumor growth. The terms angiogenesis and
Nonstandard abbreviations used: CCL, CC chemokine ligand; CCR, CC chemokine
receptor; COP, cryptogenic organizing pneumonia; CPC, circulating progenitor cell;
CXCL, CXC chemokine ligand; CXCR, CXC chemokine receptor; IPF, idiopathic pul-
monary fibrosis; UIP, usual interstitial pneumonia.
Conflict of interest: The authors have declared that no conflict of interest exists.
Citation for this article: J. Clin. Invest. 117:549–556 (2007). doi:10.1172/JCI30562.
review series
550 The Journal of Clinical Investigation http://www.jci.org Volume 117 Number 3 March 2007
vascular remodeling are often used interchangeably in the context of
both pathological and aberrant angiogenesis, as they are here.
Although inflammation and angiogenesis are distinct and separa-
ble processes, they are linked and often temporally overlap (13). The
histological appearance that is associated with all chronic fibropro-
liferative disorders is granulation-like tissue that shows prominent
vascular remodeling. The metabolic demands of granulation-like
tissue that is undergoing hyperplastic and reparative changes are
extremely high, and such tissue requires a proportionally greater
capillary blood supply than normal tissue to meet these increased
demands. Therefore, the vascular remodeling that is associated
with chronic fibroproliferative disorders is analogous to the angio-
genesis that occurs during tumorigenesis to increase the delivery of
metabolic substrates to the proliferating tumor cells.
Vascular remodeling is tightly regulated (14–28). In the local
microenvironment, the extent of vascular remodeling is deter-
mined by the balance between expression of factors that promote
angiogenesis and expression of factors that inhibit angiogenesis.
The CXC chemokine family of cytokines is unique in that different
family members regulate vascular remodeling in a disparate man-
ner. Each member of this family has four highly conserved cysteine
residues, with the first two cysteines separated by a nonconserved
aa (29, 30). A second structural domain dictates their functional
activity in regulating angiogenesis (30). The amino terminus of
several family members contains a 3-aa sequence (Glu-Leu-Arg),
known as the ELR motif, immediately before the first cysteine res-
idue (29, 30). ELR+ CXC chemokines promote angiogenesis (29,
30). By contrast, CXC chemokines that are IFN inducible and lack
the ELR motif inhibit angiogenesis (29, 30). ELR+ and ELR– CXC
chemokines bind different CXC chemokine receptors (CXCRs) on
endothelial cells, which ultimately leads to either promotion or
inhibition of angiogenesis, respectively.
Angiogenic ELR+ CXC chemokines. The ELR+ members of the CXC
chemokine family that promote angiogenesis are CXC chemokine
ligand 1 (CXCL1), CXCL2, CXCL3, CXCL5, CXCL6, CXCL7, and
CXCL8 (Table 1) (29, 30). Angiogenic factors in a local microen-
vironment can function in a direct or serial manner to promote
angiogenesis. For example, in a mouse model of Kaposi sarcoma, a
serial mechanism is as follows: VEGF activation of endothelial cells
leads to upregulation of the antiapoptotic molecule BCL2, which
in turn promotes the expression of endothelial cell–derived CXCL8
(31); the upregulated expression of CXCL8 functions in an auto-
crine and paracrine manner to maintain the angiogenic phenotype
of the endothelium (Figure 2) (31). Other serial pathways can also
promote CXCL8-dependent angiogenesis, such as the signaling
pathways induced by intracellular ROS, EGF, and HGF, which lead
to nuclear translocation of NF-κB, expression of CXCL8 in tumor
cells, and subsequent tumor-associated angiogenesis (32–35).
Although CXCL12 is not an ELR+ CXC chemokine, it has
been implicated in mediating angiogenesis through its receptor,
CXCR4 (36–39). This in turn has led to speculation that the pre-
dominant function in tumorigenesis of this ligand-receptor pair
is to mediate angiogenesis. However, several other studies have
shown that low levels of CXCL12 exist in tumors and that CXCR4
is predominately expressed by tumor cells and not endothelial
cells (40, 41). In these studies, it was found that CXCL12 did not
promote angiogenesis but instead promoted tumor metastasis
(41). A possible explanation for these different results is that
tumor cells expressing CXCR4 might be able to “out-compete”
tumor-associated endothelial cells for any CXCL12 binding due
to their higher level of expression of CXCR4. A similar mechanism
might exist in chronic fibroproliferative disorders where sur-
rounding parenchymal cells or other stromal cells such as fibro-
cytes might express CXCR4 and out-compete endothelial cells
for CXCL12. This would lead to CXCL12 exerting its profibrotic
effects through recruitment of stromal cells or fibrocytes rather
than through mediation of angiogenesis (42).
CXCR2 mediates the angiogenic effect of ELR+ CXC chemokines. There
are two CXCRs, CXCR1 and CXCR2, that are relevant to ELR+ CXC
chemokines. However, only CXCL6 and CXCL8 specifically bind
CXCR1, whereas all ELR+ CXC chemokines bind CXCR2 (43). Fur-
thermore, although expression of both CXCR1 and CXCR2 can
be detected in endothelial cells (43–45), CXCR2 has been found
to be the primary functional chemokine receptor in mediating
in vitro human lung microvascular endothelial cell chemotaxis
toward ELR+ CXC chemokines (43, 44, 46). Further studies have
confirmed the importance of CXCR2 in mediating ELR+ CXC che-
mokine–induced angiogenesis in human intestinal microvascular
endothelial cells (47). Activation of CXCR2 on endothelial cells by
CXCL8 induces rapid stress fiber assembly, chemotaxis, enhanced
Figure 1
Histopathology of normal lung tissue (A) and lung tissue from two
patients with IPF (B and C). Shown are (A) normal lung tissue (H&E
staining); (B) IPF lung tissue with severe end-stage fibrosis and honey-
comb changes (trichrome staining); and (C) IPF lung tissue with areas
of fibrosis and an area compatible with a fibroblastic focus (FF) (H&E
staining). Magnification, ×200.
review series
The Journal of Clinical Investigation http://www.jci.org Volume 117 Number 3 March 2007 551
proliferation, and phosphorylation of ERK1/2 (47). These in vitro
studies, which demonstrate the importance of CXCR2 in mediat-
ing the angiogenic effects of ELR+ CXC chemokines, have been con-
firmed in vivo, for example, in studies using an orthotropic lung
cancer model, a heterotopic renal cell cancer model, and a mouse
model of chronic airway allograft rejection (48–51).
ELR– CXC chemokines are inhibitors of angiogenesis. The angiostatic
members of the CXC chemokine family include CXCL4, CXCL9,
CXCL10, and CXCL11 (29, 30) (Table 1). CXCL9, CXCL10, and
CXCL11 (but not CXCL4) are induced by both type I and type II
IFNs (52). Moreover, the relationship among IFNs, IFN-inducible
CXC chemokines, and their biological functions are directly rel-
evant to the function of other cytokines, such as Th1 cytokines,
that lead to the stimulation of IFN expression. Therefore, through
the induction of IFN-γ, Th1 cytokines such as IL-2, IL-12, IL-15,
IL-18, and IL-23 and chemokines such as CC chemokine ligand
19 (CCL19) and CCL21 have profound effects on the production
of CXCL9, CXCL10, and CXCL11. Furthermore, this cytokine
cascade connects the Th1 cytokine profile with angiostasis and
creates the concept of immunoangiostasis (53). Interestingly, it has
recently been shown that the inflammatory lung disease sarcoid-
osis is associated with an angiostatic environment, as compared
with the angiogenic environment that is seen in IPF (54). This is
important because sarcoidosis is considered a Th1-mediated dis-
ease that resolves spontaneously in many patients (54), whereas
IPF is considered more of a Th2-mediated disease.
CXCR3 mediates the angiostatic effects of ELR– CXC chemokines. CXCR3
is the receptor that mediates the angiostatic effects of ELR– CXC
chemokines. CXCR3 exists as several variants that are generated
by alternative splicing (CXCR3A, CXCR3B, and CXCR3-alt), all of
which are involved in mediating the recruitment of Th1 cells to a
site of tissue damage as well as mediating the inhibition of angio-
genesis (55, 56). CXCR3A is the main chemokine receptor expressed
by Th1 effector cells, cytotoxic CD8+ T cells, activated B cells, and
NK cells (55). In addition, mouse endothelial cells were found
to express CXCR3 (57). Further studies, using a mouse model of
melanoma, have confirmed the observation that expression of
CXCR3 by endothelial cells is necessary for the angiostatic effects
of CXCR3 ligands, although these studies did not determine which
CXCR3 variant is necessary (58). Subsequent studies demonstrated
that, through CXCR3B, CXCR3 ligands blocked the migration and
proliferation of human microvascular endothelial cells in response
to various angiogenic factors (59). Furthermore, in a mouse model
of pulmonary fibrosis, CXCL11 inhibited vascular remodeling in a
CXCR3-dependent manner (60). Mice that received bleomycin and
were treated with CXCL11 had decreased fibrosis and decreased
intrapulmonary angiogenesis, and these decreases could be blocked
using an antibody specific to CXCR3 (60).
CXC chemokines in the regulation of angiogenesis
associated with fibroproliferation
The lung has two circulatory systems, a bronchial system that
arises from the systemic circulation and a pulmonary system that
arises directly from the pulmonary artery. Evidence exists for vas-
cular remodeling in the lung in various pathological conditions,
including pulmonary fibrosis (61–64). The angiogenic response
of the bronchial circulation is a fundamental response related to
alterations in the pulmonary vascular resistance, as can be seen
following loss of pulmonary vasculature or in pulmonary hyper-
tension (65–69). Although mice lack a bronchial circulation, vas-
cular remodeling of the systemic circulation can supply up to 15%
of the normal pulmonary blood flow within five to six days of
experimental ligation of the pulmonary artery (65). The angio-
genic factors that were instrumental in mediating angiogenesis
under these conditions were found to be ELR+ CXC chemokines
(70). Current dogma is that the pulmonary circulation has lim-
ited potential for vascular remodeling; however, Dutly and associ-
ates have recently demonstrated that the pulmonary circulation
has a major role in contributing to angiogenesis and the creation
of a new blood supply into transplanted tissue in the lung (69).
Together these findings support the notions that under ischemic
and/or hypoxic conditions, ELR+ CXC chemokines are involved in
promoting angiogenesis in the lung and that both the bronchial
and pulmonary circulations of the lung are important in promot-
ing vascular remodeling.
Vascular remodeling in IPF was originally identified by Turner-
Warwick, who, when she examined the lungs of patients with wide-
spread interstitial fibrosis, found evidence of vascular remodeling
leading to anastamoses between the systemic and pulmonary micro-
vasculatures (61). Renzoni et al. have also observed vascular remod-
eling in both IPF and the fibrosing alveolitis that is associated with
systemic sclerosis (71). Cosgrove et al. provided further support for
the concept of vascular remodeling in IPF when they demonstrated
a relative absence of vessels in the fibroblastic foci (72). Interestingly,
Table 1
Structural and functional differences of CXC chemokines in the regulation of vascular remodeling
Chemokine Effect on Relevant structural Receptor through which
angiogenesis motif effect on angiogenesis is mediated
CXCL1 (also known as GROα) Angiogenic A-T-E-L-R-C-Q-C CXCR2
CXCL2 (also known as GROβ) Angiogenic A-T-E-L-R-C-Q-C CXCR2
CXCL3 (also known as GROγ) Angiogenic V-T-E-L-R-C-Q-C CXCR2
CXCL5 (also known as ENA-78) Angiogenic L-R-E-L-R-C-V-C CXCR2
CXCL8 (also known as IL-8) Angiogenic A-K-E-L-R-C-Q-C CXCR2
CXCL4 (also known as PF4) Angiostatic D-G-D-L-Q-C-L-C CXCR3
CXCL9 (also known as MIG) Angiostatic V-R-K-G-R-C-S-C CXCR3
CXCL10 (also known as IP-10) Angiostatic S-R-T-V-R-C-T-C CXCR3
CXCL11 (also known as ITAC) Angiostatic F-K-R-G-R-C-L-C CXCR3
The underlined ELR motif indicates the conserved aa sequence of Glu-Leu-Arg in the amino terminus of CXC chemokines, which is an important structural
motif in dictating binding to the putative CXC chemokine receptor, CXCR2.
review series
552 The Journal of Clinical Investigation http://www.jci.org Volume 117 Number 3 March 2007
they also noted marked vascularity in the areas of fibrosis around
the fibroblastic foci, with numerous abnormal vessels in the regions
of severe architectural distortion. These findings are similar to those
of Renzoni and support the concept of heterogeneity of vascularity
in IPF (73). This heterogeneity is not surprising, as IPF is defined by
its regional and temporal heterogeneity.
Further studies have found that the bronchoalveolar lavage
fluid and lung tissue from patients with IPF have marked angio-
genic activity that is almost entirely attributable to overexpression
of the angiogenic ELR+ CXC chemokines CXCL5 and CXCL8 and
the relative downregulation of the angiostatic ELR– CXC chemo-
kines CXCL10 and CXCL11 (54, 60, 64, 74, 75). Furthermore, it
seems that vascular remodeling in IPF is regulated differently
than in either sarcoidosis or COP (54, 72). Both COP and sarcoid-
osis have a better prognosis than IPF, and studies aimed at under-
standing the differences in the regulation of vascular remodel-
ing in these three diseases might lead to novel insights as to the
pathogenesis of IPF.
To determine whether the imbalance in the expression of these
angiogenic and angiostatic CXC chemokines is relevant to the
pathogenesis of pulmonary fibrosis, studies have been extended to
the mouse bleomycin model. In this model, there is clear evidence
of extensive vascular remodeling during the pathogenesis of pul-
monary fibrosis (76). The amounts of CXCL2 and CXCL3 and of
CXCL10 and CXCL11 were measured in the lung during bleomy-
cin-induced pulmonary fibrosis and were found to be directly and
inversely correlated, respectively, with measures of fibrosis (77, 78).
Moreover, when endogenous CXCL2 and CXCL3 were depleted or
when exogenous CXCL10 or CXCL11 was administered to the
animals during exposure to bleomycin, a marked attenuation of
pulmonary fibrosis was observed that was entirely attributable to a
reduction in angiogenesis in the lung (60, 77, 78). Taken together,
these findings support the notions that vascular remodeling is
critical to promote the development of fibrosis and that angio-
genic and angiostatic factors, such as CXC chemokines, have an
important role in the pathogenesis of this process.
Fibrocytes, a circulating mesenchymal progenitor cell
able to induce pulmonary fibrosis
Chronic lung injury is often associated with dysregulated tissue
repair because the persistent or recurrent insults over time pro-
mote the loss of basement membrane integrity, which in turn leads
to failure of normal tissue repair and the development of fibrosis,
which is accompanied by loss of normal lung architecture. Recent
studies in mouse models have added complexity to this paradigm
of tissue injury and repair by indicating that circulating progenitor
cells can extravasate and participate, with resident mesenchymal
cells, in the repair process (52, 79, 80). The existence of circulating
progenitor cells (CPCs) has changed the perspective of the scientif-
ic community about lung repair. These cells can behave as progeni-
tor cells that extravasate into the lung and differentiate into dif-
ferent cellular lineages (42, 79, 81–83). CPCs are believed to reside
primarily in the BM and can be mobilized to enter the circulation
and subsequently to extravasate into a new tissue microniche (42,
52, 79, 80). In their new microniche, CPCs can respond to specific
environmental cues, undergo differentiation into specific cellular
lineages, integrate into the new microenvironment, and function
in a tissue-specific manner (42, 52, 79, 80).
Currently, there are three ideas (one classical and two contem-
porary) about the origin of the fibroblasts and myofibroblasts
in lung tissue that contribute to the pathogenesis of pulmonary
fibrosis (42, 84–88). The classical concept is that tissue injury in
Figure 2
Serial mechanisms of angiogenesis promoted by CXCL8. CXCL8 is
an ELR+ member of the CXC chemokine family. The ELR+ members
of this chemokine family promote angiogenesis in a direct (not shown)
or serial manner. (A) In a mouse model of Kaposi sarcoma, a serial
mechanism of angiogenesis is the following: VEGF activation of its
receptor (VEGFR) on endothelial cells leads to upregulation of the
anti-apoptotic molecule BCL2. This in turn promotes the expression
of endothelial cell–derived CXCL8, which functions in an autocrine
and paracrine manner to promote angiogenesis (31). (B) Other serial
pathways can also promote CXCL8-dependent angiogenesis, such as
the signaling pathways induced by intracellular ROS, EGF, and HGF,
which lead to nuclear translocation of NF-κB, expression of CXCL8 by
tumor cells, and subsequent tumor-associated angiogenesis (32–35).
EGFR, EGF receptor; HGFR, HGF receptor.
review series
The Journal of Clinical Investigation http://www.jci.org Volume 117 Number 3 March 2007 553
the lung induces the activation and differentiation of a population
of resident interstitial fibroblasts into myofibroblasts that migrate
into the intraalveolar space, proliferate, and express constituents
of the ECM, leading to intraalveolar and interstitial pulmonary
fibrosis (86–88). Another idea is that lung injury can induce epi-
thelial cells to transition to a mesenchymal phenotype (that is, to
gain the phenotype of fibroblasts and/or myofibroblasts) (84, 88).
The third concept is that circulating fibrocytes, derived from BM
progenitor cells, home and extravasate to sites of tissue injury and
differentiate into myofibroblasts (42, 52, 80, 85).
Although a number of cell types have been implicated in tissue
injury and repair, the fibroblast and myofibroblast have a pivotal
role in the generation of the ECM. Bucala and associates discov-
ered unique blood-borne fibroblast-like cells that expressed CD34,
CD45, and type I collagen and named these cells fibrocytes (52).
Despite expressing the common leukocyte antigen CD45, fibro-
cytes are morphologically distinct from leukocytes (52). Fibrocytes
can be cultured from a population of CD14+ cells isolated from
the peripheral blood (80). Cultured fibrocytes are spindle shaped,
express type I collagen, and neither express CD14 nor stain for
nonspecific esterase (that is, they do not have the characteristics of
monocytes and macrophages); they also lack expression of cell sur-
face markers for epithelial and endothelial cells (42, 52) (Figure 3).
Fibrocytes in the circulation and in culture express the fibroblast
markers vimentin, collagen I, collagen III, and fibronectin, but they
do not express CD3, CD4, CD8, CD16, CD19, CD25, or CD54 (52,
80, 85, 89). In addition, fibrocytes express the adhesion molecules
CD11b and CD18, the common leukocyte antigen (CD45), the pan-
myeloid antigen (CD13), HLA-DR, and the hematopoietic stem cell
antigen (CD34) (42, 52, 79, 80, 85, 89) (Figure 3). Fibrocytes in cul-
ture spontaneously express α-SMA, and this expression increases
in the presence of either TGF-β or endothelin, compatible with the
differentiation of fibrocytes into myofibroblasts (42, 79, 80, 85, 89).
This is associated with loss of expression of CD34 (42, 79, 89, 90)
and CD45 (42), supporting the notion that with differentiation,
these cells lose their stem and common leukocyte markers.
Fibrocytes have been found to be pleiotropic in their behavior
and possess several functions that are relevant to fibrosis. They are
potent APCs and can recruit and activate T cells that might play
a role in the early injury that leads to the development of fibrosis
(91). Fibrocytes can promote angiogenesis by producing various
angiogenic factors (92). They also produce various cytokines that
are potent inducers of collagen production (85, 93) and have been
shown to play an important role in the development of fibrosis in
animal models of pulmonary fibrosis (42, 82, 83). Interestingly,
Rojas and coworkers demonstrated the importance of intact BM
in the repair of injured lung, suggesting that there is a popula-
tion of cells in the BM that are important in the attenuation of
lung injury and fibrosis (94). Similarly Ortiz et al. have shown
that BM-derived mesenchymal cells have the ability to develop
an epithelial phenotype and attenuate bleomycin-induced lung
injury (95). The specific conditions that stimulate the release and
recruitment of reparative cells as opposed to fibrosis-promoting
fibrocytes remain to be determined.
Chemokine receptors in fibrocyte trafficking to the lung. Classic cell
trafficking has been well described for leukocytes, but it is an area
of relatively new investigation for fibrocytes. The complicated,
multi-step process of leukocyte trafficking from the BM into
the tissues involves specific combinations of chemokine ligands
and chemokine receptors to orchestrate these events (96). In the
lung, different expression patterns of chemokine ligands occur at
defined points after injury to mediate recruitment of cells includ-
ing leukocytes and fibrocytes.
Human fibrocytes express the chemokine receptors CC chemo-
kine receptor 3 (CCR3), CCR5, CCR7, and CXCR4 (42, 80, 89). By
contrast, mouse fibrocytes express CCR2, CCR7, and CXCR4 (42,
80, 89, 97). Fibrocytes that express CXCR4 migrate in response
to CXCL12 under specific conditions in vitro, and the CXCL12-
CXCR4 axis has an important role in mediating fibrocyte extrav-
asation into the lungs so that fibrocytes can contribute to the
pathology of pulmonary fibrosis (Figure 4) (42). Fibrocytes also
express CCR7, which is a chemokine receptor that is important
for DC and T cell migration in response to the CC chemokines
CCL19 and CCL21 (98). A population of fibrocytes that express
CCR7 and that are distinct from the CXCR4-expressing fibrocytes
has been identified in a mouse model of pulmonary fibrosis (42).
However, intrapulmonary recruitment of CXCR4+ fibrocytes is
markedly greater than the intrapulmonary recruitment of CCR7+
fibrocytes (42). Similarly, CCR2 was shown to play a role in the
recruitment of fibrocytes in a model of FITC-induced lung injury,
and this seemed to be mediated by CCL12 (82, 83). Interestingly,
in a model of renal fibrosis, CCR7 seemed to have an important
role in the recruitment of fibrocytes to the kidney (99). Therefore,
at least in mice, CXCR4 and CCR2 seem to mediate recruitment
of fibrocytes to the lung, whereas CCR7 might be important for
the recruitment of fibrocytes to the kidney (42, 83). If indeed these
cells can traffic to human lung, become activated, proliferate, and
differentiate into myofibroblasts, then preventing their recruit-
ment would impact the pathogenesis of pulmonary fibrosis.
Fibrocytes contribute to pulmonary fibrosis. Depletion of CXCL12 in
the bleomycin-induced pulmonary fibrosis mouse model directly
correlated with decreased deposition of ECM and decreased detec-
tion of cells expressing α-SMA in the lung (42). This suggests that
fibrocytes directly contribute to the development of pulmonary
fibrosis. In another study, Moore and colleagues examined the
contribution of fibrocytes to fibrosis in a FITC-induced mouse
model of pulmonary fibrosis (83). In this study, fibrocytes in the
bronchoalveolar lavage fluid and lung tissue were analyzed. They
found that populations of fibrocytes expressed CCR2, CCR5,
CCR7, and CXCR4. The finding of high expression of CCR2 by
mouse fibrocytes is in contrast to what is known about human
Figure 3
Markers associated with human fibrocytes. Human fibrocytes express
ECM components (type I collagen, type III collagen, and vimentin). They
also express a range of cell surface markers, including the common
leukocyte antigen CD45, the hematopoietic stem cell antigen CD34, the
adhesion molecules CD11b and CD18, the pan-myeloid antigen CD13,
and the chemokine receptors CCR3, CCR5, CCR7, and CXCR4.
review series
554 The Journal of Clinical Investigation http://www.jci.org Volume 117 Number 3 March 2007
fibrocytes, which express low levels of CCR2 after isolation (100).
Fibrocytes isolated from mouse lungs expressed CCR2, migrated
toward the CCR2 ligands, CCL2 and CCL12, and lost expression of
CCR2 when cultured in vitro (83). Fibrocyte recruitment has also
been shown to be reduced in Ccr2–/– mice exposed to intrapulmo-
nary FITC (83). Recruitment of lung fibrocytes in Ccr2–/– mice was
restored if the mice received BM from CCR2-sufficient mice. Con-
versely, if wild-type mice received a Ccr2–/– BM transplant, the mice
were protected from FITC-induced fibrosis (83). Interestingly, the
same authors did not find the same results with mice lacking the
CCR2 ligand CCL2; they instead found that CCL12 was the most
important CCR2 ligand for the recruitment of CCR2+ fibrocytes
to the lung in this model of pulmonary fibrosis (82). However,
CCL12 is likely to only be relevant to mouse biology, as no human
homolog has been identified.
To further confirm that fibrocytes can differentiate into myofi-
broblasts in vivo, Mori and colleagues studied skin wound heal-
ing in chimeric mice in which only BM-derived cells expressed
GFP. The GFP+ BM-derived fibrocytes in wounds coexpressed
GFP and α-SMA, indicating that fibrocytes were derived from the
BM (101). BM-derived progenitor myofibroblasts have also been
found in pulmonary fibrosis after lung irradiation in mice (102).
Hashimoto et al. also used a GFP chimeric model and found that,
following bleomycin administration, there were abundant GFP+
fibroblasts in the lung (103). Surprisingly, no GFP+ myofibroblasts
were detected. Notwithstanding this study, most in vitro and in
vivo studies of fibrocytes suggest that fibrocytes recruited from
the peripheral circulation ultimately develop an α-SMA+ pheno-
type and contribute to the development of pulmonary fibrosis
in the mouse. This is compatible with the in vitro findings for
human fibrocytes, and therefore it is conceivable that fibrocytes
contribute to the pathogenesis of pulmonary fibrosis in humans.
Interestingly, it has recently been shown that both CXCR4 and
CCR7 are expressed in human pulmonary fibrosis specimens (104,
105). Yang et al. demonstrated increased expression of CXCL12
and CXCR4 in both familial and sporadic pulmonary fibrosis as
compared with normal specimens (105). By contrast, Choi et al.
described increased expression of CCR7 but not CXCR4 in IPF
specimens as compared with normal lung tissue adjacent to
tumors (104). The difference in the normal specimens used as con-
trols in these two studies (104, 105) might explain the differences
in the findings. Therefore, although there is no direct evidence of a
role for fibrocytes in the pathogenesis of human pulmonary fibro-
sis, the presence of the ligands and receptors that are necessary for
the recruitment of fibrocytes is circumstantial evidence for their
playing an important role.
Figure 4
The role of the CXCL12-CXCR4 biological axis in fibrocyte extravasation in pulmonary fibrosis. Lung-derived factors (such as GM-CSF, G-CSF,
and M-CSF) generated under conditions of lung injury communicate with the BM to expand the number of fibrocytes in the BM and to mobilize
fibrocytes that express CXCR4 into the circulation. CXCR4-expressing fibrocytes traffic through the circulation and extravasate into the lung in
response to the CXCR4 ligand CXCL12, which is produced during the pathogenesis of fibrosis.
review series
The Journal of Clinical Investigation http://www.jci.org Volume 117 Number 3 March 2007 555
Conclusions
Normal wound repair requires a coordinated sequence of events
that includes angiogenesis and recruitment of fibrocytes, which
regress when healing is complete. By contrast, the development
of fibrosis is associated with aberrant repair, persistence of col-
lagen deposition, and the development of vascular remodeling.
The CXC chemokines are a unique cytokine family that has the
potential to regulate both fibrocyte recruitment and vascular
remodeling. CXC chemokines can exhibit either angiogenic or
angiostatic biological activity, and the balance of their expres-
sion seems to be important in the regulation of vascular remod-
eling associated with chronic fibroproliferative disorders in the
lung. Similarly, the ability of fibrocytes to differentiate along the
mesenchymal lineage has created a novel paradigm related to
their role in mediating pulmonary fibrosis. The CXCL12-CXCR4
biological axis and perhaps other chemokine–chemokine recep-
tor interactions seem to be important for the trafficking and
extravasation of fibrocytes into the lung during the pathogenesis
of pulmonary fibrosis (Figure 4).
However, several questions remain to be fully answered, such as,
What other signals are involved in the recruitment of fibrocytes?
Are signals different between humans and mice? What factors and
signaling pathways are involved in the differentiation of fibro-
cytes into myofibroblasts? Does the microniche in the lung deter-
mine whether the fibrocyte differentiates into a myofibroblast or
another mesenchymal lineage cell? Furthermore, it remains to
be determined whether, similar to the mouse models, there are
separate populations of BM-derived cells that are important for
repair instead of the promotion of fibrosis. If indeed there are
distinct populations of BM-derived mesenchymal cells, what fac-
tors are involved in the recruitment of these distinct populations?
All of these issues are critical to our understanding of fibrosis
and should be addressed in order to design therapeutic strategies
to attenuate fibrocyte function and vascular remodeling, thereby
preventing them contributing to fibrotic disorders of the lungs.
Acknowledgments
This work was supported in part by NIH grants HL66027,
HL087849, P50 HL67665, and CA87879 (to R.M. Strieter) and
HL03906 and P50 HL67665 and AR 055075 (to M.P. Keane).
Address correspondence to: Robert M. Strieter, Department of
Medicine, Hospital Dr., 6th floor Outpatient Clinics Building,
Room 6560, University of Virginia School of Medicine, Charlot-
tesville, Virginia 22908, USA. Phone: (434) 982-6999; Fax: (434)
243-0399; E-mail: strieter@virginia.edu.
1. Coultas, D.B., Zumwalt, R.E., Black, W.C., and
Sobonya, R.E. 1994. The epidemiology of inter-
stitial lung diseases. Am. J. Respir. Crit. Care Med.
150:967–972.
2. Perez, A., Rogers, R.M., and Dauber, J.H. 2003. The
prognosis of idiopathic pulmonary fibrosis. Am. J.
Respir. Cell Mol. Biol. 29(3 Suppl.):S19–S26.
3. Allam, J.S., and Limper, A.H. 2006. Idiopathic pul-
monary fibrosis: is it a familial disease? Curr. Opin.
Pulm. Med. 12:312–317.
4. Steele, M.P., et al. 2005. Clinical and pathologic
features of familial interstitial pneumonia. Am. J.
Respir. Crit. Care Med. 172:1146–1152.
5. du Bois, R. 1997. Diffuse lung disease: a view for the
future. Sarcoidosis Vasc. Diffuse Lung Dis. 14:23–30.
6. Selman, M., King, T.E., and Pardo, A . 2001. Idio-
pathic pulmonary fibrosis: prevailing and evolving
hypotheses about its pathogenesis and implica-
tions for therapy. Ann. Intern. Med. 134:136–151.
7. Gauldie, J. 2002. Pro. Inflammatory mechanisms
are a minor component of the pathogenesis of
idiopathic pulmonary fibrosis. Am. J. Respir. Crit.
Care Med. 165:1205–1206.
8. Strieter, R.M. 2002. Con. Inflammatory mecha-
nisms are not a minor component of the patho-
genesis of idiopathic pulmonary fibrosis. Am. J.
Respir. Crit. Care Med. 165:1206–1207; discussion
1207–1208.
9. Cool, C.D., et al. 2006. Fibroblast foci are not dis-
crete sites of lung injury or repair: the fibroblast
reticulum. Am. J. Respir. Crit. Care Med. 174:654–658.
10. Adamson, I.Y., and Bowden, D.H. 1974. The patho-
genesis of bleomycin-induced pulmonary fibrosis
in mice. Am. J. Pathol. 77:185–197.
11. Chandler, D.B. 1990. Possible mechanisms of bleo-
mycin-induced fibrosis. Clin. Chest Med. 11:21–30.
12. Polverini, P. 2002. Angiogenesis in health and dis-
ease: insights into basic mechanisms and therapeu-
tic opportunities. J. Dent. Educ. 66:962–975.
13. Jackson, J.R., et al. 1997. The codependence of
angiogenesis and chronic inflammation. FASEB J.
11:457–465.
14. Auerbach, W., and Auerbach, R. 1994. Angiogenesis
inhibition: a review. Pharmacol. Ther. 63:265–311.
15. Auerbach, R., Auerbach, W., and Polakowski, I.
1991. Assays for angiogenesis: a review. Pharmacol.
Ther. 51:1–11.
16. Ziche, M., Morbi delli, L., and Donnin i, S . 19 96.
Angiogenesis. Exp. Nephrol. 4:1–14.
17. Pluda, J.M. 1997. Tumor-associated angiogenesis:
mechanisms, clinical implications, and therapeutic
strategies. Semin. Oncol. 24:203–218.
18. Pluda, J. M., and Park inson, D. R. 1996. Cli nical
implications of tumor-associated neovasculariza-
tion and current antiangiogenic strategies for the
treatment of malignancies of pancreas. Cancer.
78:680–687.
19. Gastl, G., et al. 1997. Angiogenesis as a target for
tumor treatment. Oncology. 54:177–184.
20. Risau, W. 1998. Angiogenesis is coming of age. Circ.
Res. 82:926–928.
21. Risau, W. 1997. Mechanisms of angiogenesis.
Nature. 386:671–674.
22. Hotfi lder, M., N owak-Got tl, U., an d Wolff, J. E.
1997. Tumorangiogenesis: a network of cytokines.
Klin. Padiatr. 209:265–270.
23. Hui, Y.F., and Ignoffo, R.J. 1998. Angiogenesis
inhibitors. A promising role in cancer therapy.
Cancer Pract. 6:60–62.
24. Kumar, R., and Fidler, I.J. 1998. Angiogenic mol-
ecules and cancer metastasis. In Vivo. 12:27–34.
25. Zetter, B.R. 1988. Angiogenesis. State of the art.
Chest. 93(3 Suppl.):159S–166S.
26. Zetter, B.R. 1998. Angiogenesis and t umor metas-
tasis. Annu. Rev. Med. 49:407–424.
27. Lund, E.L., Spang-Thomsen, M., Skovgaard-
Poulsen, H., and Kristjansen, P.E. 1998. Tumor
angiogenesis — a new therapeutic target in glio-
mas. Acta Neurol. Scand. 97:52–62.
28. Lund, E.L., a nd Kristjansen, P.E. 1999. Neovas cu-
larization of tumors. New therapeutic possibilities
[In Danish]. Ugeskr Laeger. 161:2929–2933.
29. Belperio, J.A., et al. 2000. CXC chemokines in
angiogenesis. J. Leukoc. Biol. 68:1–8.
30. Strieter, R.M., et al. 1995. The functional role of the
ELR motif in CXC chemokine-mediated angiogen-
esis. J. Biol. Chem. 270:27348–27357.
31. Nor, J.E., et al . 2001. Up-r egulati on of Bcl-2 in
microvascular endothelial cells enhances intratu-
moral angiogenesis and accelerates tumor growth.
Cancer Res. 61:2183–2188.
32. Dong, G., et al. 2001. Hepatocyte growth factor/
scatter factor-induced activation of MEK and PI3K
signal pathways contributes to expression of pro-
angiogenic cytokines interleukin-8 and vascular
endothelial growth factor in head and neck squa-
mous cell carcinoma. Cancer Res. 61:5911–5918.
33. Hirata, A., et al. 2002. ZD1839 (Iressa) induces anti-
angiogenic effects through inhibition of epidermal
growth factor receptor tyrosine kinase. Cancer Res.
62:2554–2560.
34. Strieter, R.M. 2005. Masters of angiogenesis. Nat.
Med. 11:925–927.
35. Strieter, R.M., et al. 2005. CXC chemokines in angio-
genesis. Cytokine Growth Factor Rev. 16:593–609.
36. Bachelder, R.E., Wendt, M.A., and Mercurio, A.M.
2002. Vascular endothelial growth factor promotes
breast carcinoma invasion in an autocrine manner
by regulating the chemokine receptor CXCR4. Can-
cer Res. 62:7203–7206.
37. Salcedo, R., and Oppenheim, J.J. 2003. Role of
chemokines in angiogenesis: CXCL12/SDF-1 and
CXCR4 interaction, a key regulator of endothelial
cell responses. Microcirculation. 10:359–370.
38. Kijowski, J., et al. 2001. The SDF-1–CXCR4 axis
stimulates VEGF secretion and activates integrins
but does not affect proliferation and survival in
lymphohematopoietic cells. Stem Cells. 19:453–466.
39. Salcedo, R., et al. 1999. Vascular endothelial growth
factor and basic fibroblast growth factor induce
expression of CXCR4 on human endothelial cells: in
vivo neovascularization induced by stromal-derived
factor-1alpha. Am. J. Pathol. 154:1125–1135.
40. Schrader, A.J., et al. 2002. CXCR4/CXCL12 expres-
sion and signalling in kidney cancer. Br. J. Cancer.
86:1250–1256.
41. Phillips, R.J., et al. 2003. The stromal d erived fac-
tor-1/CXCL12-CXC chemokine receptor 4 biologi-
cal axis in non-small cell lung cancer metastases.
Am. J. Respir. Crit. Care Med. 167:1676–1686.
42. Phillips, R.J., et al. 2004. Circulating fibrocytes traf-
fic to the lungs in response to CXCL12 and mediate
fibrosis. J. Clin. Invest. 114:438–446. doi:10.1172/
JCI200420997.
43. Addison, C.L., et al. 2000. The CXC chemokine
receptor 2, CXCR2, is the putative receptor for
ELR(+) CXC chemokine-induced angiogenic activ-
ity. J. Immunol. 165:5269–5277.
44. Murdoch, C., Monk, P.N., and Finn, A. 1999.
CXC chemokine receptor expression on human
endothelial cells. Cytokine. 11:704–712.
review series
556 The Journal of Clinical Investigation http://www.jci.org Volume 117 Number 3 March 2007
45. Salcedo, R., et al. 2000. Differential expression
and responsiveness of chemokine receptors
(CXCR1-3) by human microvascular endothelial
cells and umbilical vein endothelial cells. FASEB J.
14:2055–2064.
46. Schraufstatter, I.U., et al. 2003. IL-8-mediated cell
migration in endothelial cells depends on cathep-
sin B activity and transactivation of the epidermal
growth factor receptor. J. Immunol. 171:6714–6722.
47. Heidemann, J., et al. 2003. Angiogenic effects of
interleukin 8 (CXCL8) in human intestinal micro-
vascular endothelial cells are mediated by CXCR2.
J. Biol. Chem. 278:8508–8515.
48. Keane, M.P., et al. 2004. Depletion of CXCR2 inhib-
its tumor growth and angiogenesis in a murine
model of lung cancer. J. Immunol. 172:2853–2860.
49. Mestas, J., et al. 2005. The role of CXCR2/CXCR2
ligand biological axis in renal cell carcinoma.
J. Immunol. 175:5351–5357.
50. Belperio, J.A., et al. 2005. Role of CXCR2/CXCR2
ligands in vascular remodeling during bronchiolitis
obliterans syndrome. J. Clin. Invest. 115:1150–1162.
doi:10.1172/JCI200524233.
51. Wislez, M., et al. 2006. High expression of ligands
for chemokine receptor CXCR2 in alveolar epithe-
lial neoplasia induced by oncogenic kras. Cancer
Res. 66:4198–4207.
52. Bucala, R., et al. 1994. Circulating fibrocytes define
a new leukocyte subpopulation that mediates tis-
sue repair. Mol. Med. 1:71–81.
53. Pan, J., et al. 2006. CXCR3/CXCR3 ligand biological
axis impairs RENCA tumor growth by a mechanism
of immunoangiostasis. J. Immunol. 176:1456–1464.
54. Antoniou, K.M., et al. 2006. Different angiogenic
activity in pulmonary sarcoidosis and idiopathic
pulmonary fibrosis. Chest. 130:982–988.
55. Loetscher, M., et al. 1998. Lymphocyte-specific
chemokine receptor CXCR3: regulation, chemo-
kine binding and gene localization. Eur. J. Immunol.
28:3696–3705.
56. Ehlert, J.E., et al. 2004. Identif ication and partial
characterization of a variant of human CXCR3
generated by posttranscriptional exon skipping.
J. Immunol. 173:6234–6240.
57. Soto, H., et al. 1998. The CC chemokine 6Ckine
binds the CXC chemokine receptor CXCR3. Proc.
Natl. Acad. Sci. U. S. A. 95:8205–8210.
58. Yang, J., and Richmond, A. 2004. The angio-
static activity of interferon-inducible protein-10/
CXCL10 in human melanoma depends on binding
to CXCR3 but not to glycosaminoglycan. Mol. Ther.
9:846–855.
59. Romagnani, P., et al. 2001. Cell cycle-dependent
expression of CXC chemokine receptor 3 by
endothelial cells mediates angiostatic activity.
J. Clin. Invest. 107:53–63.
60. Burdick, M.D., et al. 2005. CXCL11 attenuates
bleomycin-induced pulmonary fibrosis via inhibi-
tion of vascular remodeling. Am. J. Respir. Crit. Care
Med. 171:261–268.
61. Turner-Warwick, M. 1963. Precapillary systemic-
pulmonary anastomoses. Thorax. 18:225–237.
62. Keane, M.P., et al. 2002. Imbalance in the expres-
sion of CXC chemokines correlates with bron-
choalveolar lavage fluid angiogenic activity and
procollagen levels in acute respiratory distress syn-
drome. J. Immunol. 169:6515–6521.
63. Keane, M. P., et al . 2001. ENA-78 is an important
angiogenic factor in idiopathic pulmonary fibrosis.
Am. J. Respir. Crit. Care Med. 164:2239–2242.
64. Keane, M.P., et al. 1997. The CXC chemokines, IL-8
and IP-10, regulate angiogenic activity in idiopath-
ic pulmonary fibrosis. J. Immunol. 159:1437–1443.
65. Mitzner, W., Lee, W., Georgakopoulos, D., and
Wagner, E. 2000. Angiogenesis in the mouse lung.
Am. J. Pathol. 157:93–101.
66. Charan, N.B., and Carvalho, P. 1997. Angiogenesis in
bronchial circulatory system after unilateral pulmo-
nary artery obstruction. J. Appl. Physiol. 82:284–291.
67. Schlaepfer, K. 1924. Ligation of the pulmonary
artery of one lung with and without resection of
the phrenic nerve. Arch. Surg. 9:25–94.
68. Michel, R.P., Hakim, T.S., and Petsikas, D. 1990.
Segmental vascular resistance in postobstruc-
tive pulmonary vasculopathy. J. Appl. Physiol.
69:1022–1032.
69. Dutly, A.E., et al. 2005. A novel model for post-
transplant obliterative airway disease reveals
angiogenesis from the pulmonary circulation. Am.
J. Transplant. 5:248–254.
70. Srisum a, S., et al. 20 03. Iden tific ation of ge nes
promoting angiogenesis in mouse lung by tran-
scriptional profiling. Am. J. Respir. Cell Mol. Biol.
29:172–179.
71. Renzoni, E.A., et al. 2003. Interstitial vascularity
in fibrosing alveolitis. Am. J. Respir. Crit. Care Med.
167:438–443.
72. Cosgrove, G.P., et al. 2004. Pigment epithelium-
derived factor in idiopathic pulmonary fibrosis:
a role in aberrant angiogenesis. Am. J. Respir. Crit.
Care Med. 170:242–251.
73. Keane, M.P. 2004. Angiogenesis and pulmonary
fibrosis: feast or famine? Am. J. Respir. Crit. Care
Med. 170:207–209.
74. Keane, M. P., et al . 2001. ENA-78 is an important
angiogenic factor in idiopathic pulmonayr fibrosis.
Am. J. Respir. Crit. Care Med. 164:2239–2242.
75. Belperio, J.A., et al. 2003. Role of CXCL9/CXCR3
chemokine biology during pathogenesis of acute
lung allograft rejection. J. Immunol. 171:4844–4852.
76. Peao, M.N., Aguas, A.P., de Sa, C.M., and Grande,
N.R. 1994. Neoformation of blood vessels in associ-
ation with rat lung fibrosis induced by bleomycin.
Anat. Rec. 238:57–67.
77. Keane, M.P., et al. 1999. Neutralization of the CXC
chemokine, macrophage inflammatory protein-2,
attenuates bleomycin-induced pulmonary fibrosis.
J. Immunol. 162:5511–5518.
78. Keane, M.P., et al. 1999. IFN-gamma-inducible pro-
tein-10 attenuates bleomycin-induced pulmonary
fibrosis via inhibition of angiogenesis. J. Immunol.
163:5686–5692.
79. Schmidt, M., et al. 2003. Identification of circulat-
ing fibrocytes as precursors of bronchial myofibro-
blasts in asthma. J. Immunol. 171:380–389.
80. Abe, R., et al. 2001. Peripheral blood f ibrocytes:
differentiation pathway and migration to wound
sites. J. Immunol. 166:7556–7562.
81. Gomperts, B.N., et al. 2006. Circulating progenitor
epithelial cells traffic via CXCR4/CXCL12 in response
to airway injury. J. Immunol. 176:1916–1927.
82. Moore, B.B., et al. 2006. The role of CCL12 in the
recruitment of fibrocytes and lung fibrosis. Am. J.
Respir. Cell Mol. Biol. 35:175–181.
83. Moore, B.B., et al. 2005. CCR2-mediated recruit-
ment of fibrocytes to the alveolar space after fibrot-
ic injury. Am. J. Pathol. 166:675–684.
84. Iwano, M., et al. 2002. Evidence that fibroblasts
derive from epithelium during tissue fibrosis. J. Clin.
Invest. 110:341–350. doi:10.1172/JCI200215518.
85. Metz, C.N. 2003. Fibrocytes: a unique cell popula-
tion implicated in wound healing. Cell. Mol. Life Sci.
60:1342–1350.
86. Fukuda, Y., et al . 198 7. The role of intraal veolar
fibrosis in the process of pulmonary structural
remodeling in patients with diffuse alveolar dam-
age. Am. J. Pathol. 126:171–182.
87. Marshall, R., Bellingan, G., and Laurent, G. 1998.
The acute respiratory distress syndrome: fibrosis in
the fast lane. Thorax. 53:815–817.
88. Kalluri, R., and Neilson, E.G. 2003. Epithelial-
mesenchymal transition and its implications for
fibrosis. J. Clin. Invest. 112:1776–1784. doi:10.1172/
JCI200320530.
89. Quan, T.E., et al. 2004. Circulating fibrocytes: col-
lagen-secreting cells of the peripheral blood. Int. J.
Biochem. Cell Biol. 36:598–606.
90. Chauhan, H., et al. 2003. There is more than one
kind of myofibroblast: analysis of CD34 expression
in benign, in situ, and invasive breast lesions. J. Clin.
Pathol. 56:271–276.
91. Chesney, J., Bacher, M., Bender, A., and Bucala, R.
1997. The peripheral blood fibrocyte is a potent anti-
gen-presenting cell capable of priming naive T cells
in situ. Proc. Natl. Acad. Sci. U. S. A. 94:6307–6312.
92. Hart lapp , I., e t al. 2001. Fibr ocyt es in duce an
angiogenic phenotype in cultured endothelial
cells and promote angiogenesis in vivo. FASEB J.
15:2215–2224.
93. Chesney, J., et al. 1998. Regulated production of type
I collagen and inflammatory cytokines by periph-
eral blood fibrocytes. J. Immunol. 160:419–425.
94. Mora, A.L., et al. 2006. Activation of alveolar
macrophages via the alternative pathway in herpes-
virus-induced lung fibrosis. Am. J. Respir. Cell Mol.
Biol. 35:466–473.
95. Ortiz, L.A., et al. 2003. Mesenchymal stem cell
engraftment in lung is enhanced in response to
bleomycin exposure and ameliorates its fibrotic
effects. Proc. Natl. Acad. Sci. U. S. A. 100:8407–8411.
96. Smith, R.E., Strieter, R.M., Phan, S.H., and Kunkel,
S.L. 1996. CC chemokines: novel mediators of the
profibrotic inflammatory response to bleomycin
challenge. Am. J. Respir. Cell Mol. Biol. 15:693–702.
97. Moore, B.B., et al. 2005. Bleomycin-induced E pros-
tanoid receptor changes alter fibroblast responses
to prostaglandin E2. J. Immunol. 174:5644–5649.
98. Jang, M.H., et al. 2006. CCR7 is critically important
for migration of dendritic cells in intestinal lamina
propria to mesenteric lymph nodes. J. Immunol.
176:803–810.
99. Sakai, N., et al. 2006. Secondary lymphoid tissue
chemokine (SLC/CCL21)/CCR7 signaling regu-
lates fibrocytes in renal f ibrosis. Proc. Natl. Acad.
Sci. U. S. A. 103:14098–14103.
100. Hong, K.M., et al. 2005. Characterization of human
fibrocytes as circulating adipocyte progenitors and
the formation of human adipose tissue in SCID
mice. FASEB J. 19:2029–2031.
101. Mori, L., et al. 2005. Fibrocytes contribute to the
myofibroblast population in wounded skin and
originate from the bone marrow. Exp. Cell Res.
304:81–90.
102. Epperly, M.W., Guo, H., Gretton, J.E., and Green-
berger, J.S. 2003. Bone marrow origin of myofi-
broblasts in irradiation pulmonary fibrosis. Am. J.
Respir. Cell Mol. Biol. 29:213–224.
103. Hashimoto, N., et al. 2004. Bone marrow-derived
progenitor cells in pulmonary fibrosis. J. Clin.
Invest. 113:243–252. doi:10.1172/JCI200418847.
104. Choi, E.S., et al. 2006. Focal interstitial CC chemo-
kine receptor 7 (CCR7) expression in idiopathic
interstitial pneumonia. J. Clin. Pathol. 59:28–39.
105. Yang, I.V., et al. 2007. Gene expression profiling of
familial and sporadic cases of interstitial pneumo-
nia. Am. J. Respir. Crit. Care Med. In press.
