Fibrocytes in health and disease

Fibrocytes are circulating mesenchymal progenitor cells that participate in tissue responses to injury and invasion. Accumulating knowledge from animal models regarding the differentiation, trafficking, and function of these cells implicates them in the development of diseases characterized by chronic inflammation and excessive collagen deposition. Recent data obtained from the clinical setting suggests that the enumeration of circulating fibrocytes may be a biomarker for disease progression in chronic lung diseases including asthma and pulmonary fibrosis. A greater understanding of the immunologic mediators that influence fibrocyte biology suggests new opportunities for therapeutic manipulation of these cells in fibrogenesis. This review integrates new developments in the cellular and molecular biology of fibrocytes with current concepts regarding the etiopathogenesis of fibrosing disorders. Fibrocytes are circulating mesenchymal progenitor cells that participate in tissue responses to injury and invasion. Accumulating knowledge from animal models regarding the differentiation, trafficking, and function of these cells implicates them in the development of diseases characterized by chronic inflammation and excessive collagen deposition. Recent data obtained from the clinical setting suggests that the enumeration of circulating fibrocytes may be a biomarker for disease progression in chronic lung diseases including asthma and pulmonary fibrosis. A greater understanding of the immunologic mediators that influence fibrocyte biology suggests new opportunities for therapeutic manipulation of these cells in fibrogenesis. This review integrates new developments in the cellular and molecular biology of fibrocytes with current concepts regarding the etiopathogenesis of fibrosing disorders. Tissue integrity is maintained by the coordinated activation of cellular responses that counter pathogen invasion and maintain normal architecture. In most circumstances, host immunity acts to restore tissue homeostasis and function. However, in the setting of persistent invasion, injury, immunodeficiency, vascular insufficiency or metabolic abnormalities, reparative processes do not proceed normally and pathologic remodeling occurs [1Wilson M.S. Wynn T.A. Pulmonary fibrosis: pathogenesis, etiology and regulation.Mucosal Immunol. 2009; 2: 103-121Crossref PubMed Scopus (496) Google Scholar]. This process, which results in the replacement of normal tissue components with inflammatory cells and connective tissue scar, is the basis for the pathologic changes of asthma [2Lee C.G. Homer R.J. 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Although the current paradigm of tissue repair describes a sequential process that proceeds from injury to inflammation, followed by resolution and repair, it is clear that cells recruited during the early response to invasion and injury play a critical role in the ensuing progression of the repair response.Until recently, it was considered that both normal and dysregulated repair responses originated from the recruitment, proliferation, and activation of local connective tissue cells [4Liu Y. Renal fibrosis: new insights into the pathogenesis and therapeutics.Kidney Int. 2006; 69: 213-217Crossref PubMed Scopus (882) Google Scholar]. Research performed during the last several years, however, now supports the contention that connective-tissue/extracellular matrix (ECM)−producing cells also develop by alternate pathways, such as the reactivation of an embryonic epithelial-mesenchymal pathway [8Kim K.K. Wei Y. Szekeres C. et al.Epithelial cell alpha3beta1 integrin links beta-catenin and Smad signaling to promote myofibroblast formation and pulmonary fibrosis.J Clin Invest. 2009; 119: 213-224PubMed Google Scholar] or the recruitment of bone marrow−derived progenitor cells [9Pereira R.F. Halford K.W. O'Hara M.D. et al.Cultured adherent cells from marrow can serve as long-lasting precursor cells for bone, cartilage, and lung in irradiated mice.Proc Natl Acad Sci U S A. 1995; 92: 4857-4861Crossref PubMed Scopus (823) Google Scholar]. Interestingly, the notion of monocytic fibroblast precursors derived from the circulation was first proposed >150 years ago following the careful microscopic observations of James Paget. Blood-borne, connective tissue cell precursors are described in the writings of Cohnheim, Fischer, and Maximow [10Cohnheim J. Ueber Entzundung und Eiterung (About inflammation and suppuration).Path Anat Physiol Klin Med. 1867; 40: 1-79Crossref Scopus (257) Google Scholar, 11Fischer A.C. Transformation outside of organism of mononuclears into fibroblasts.Compt Rend Soc Biol. 1925; 92: 109-112Google Scholar, 12Maximow A. Cultures of blood leucocytes. From lymphocyte and monocyte to connective tissue.Arch Exp Zellforsch. 1928; 5: 169-268Google Scholar] and this area has been an active focus of debate for many years, and in many respects it remains so.Fibrocyte characteristicsFibrocyte discovery and initial characterizationThe "fibrocyte" was described in 1994 as a circulating, bone marrow−derived cell with the ability to adopt a mesenchymal phenotype [13Bucala R. Spiegel L.A. Chesney J. Hogan M. Cerami A. Circulating fibrocytes define a new leukocyte subpopulation that mediates tissue repair.Mol Med. 1994; 1: 71-81Crossref PubMed Google Scholar]. This cell bears features of both fibroblasts and monocytes, and this combination of connective tissue cell and myeloid features allows its identification by a number of markers. Fibrocytes express the stem cell marker CD34, the panhematopoietic marker CD45, monocyte markers such as CD14 and CD11, and they produce components of the connective tissue matrix including collagen-1, collagen-III, and vimentin [14Medbury H. Role of fibrocytes in atherogenesis.in: Bucala R. Fibrocytes: new insights into tissue repair and systemic fibroses. World Scientific Publishing Co. Pte. Ltd, Singapore2007: 175-194Crossref Scopus (4) Google Scholar]. Originally identified by CD34 and collagen-1 co-expression [13Bucala R. Spiegel L.A. Chesney J. Hogan M. Cerami A. Circulating fibrocytes define a new leukocyte subpopulation that mediates tissue repair.Mol Med. 1994; 1: 71-81Crossref PubMed Google Scholar], fibrocytes may be identified by dual positivity of CD34 or CD45 and collagen-1 or pro-collagen−1. The expression of the progenitor cell marker CD34 engendered the notion that fibrocytes constitute a bone marrow−derived fibroblast population that circulates in the peripheral blood [14Medbury H. Role of fibrocytes in atherogenesis.in: Bucala R. Fibrocytes: new insights into tissue repair and systemic fibroses. World Scientific Publishing Co. Pte. Ltd, Singapore2007: 175-194Crossref Scopus (4) Google Scholar]. Human and murine fibrocytes are easily isolated by the expansion of adherent peripheral blood mononuclear on either plastic or fibronectin-coated plates [15Abe R. Donnelly S.C. Peng T. Bucala R. Metz C.N. Peripheral blood fibrocytes: differentiation pathway and migration to wound sites.J Immunol. 2001; 166: 7556-7562Crossref PubMed Scopus (911) Google Scholar]. Although enrichment for CD14+ peripheral blood cells increases fibrocyte outgrowth [15Abe R. Donnelly S.C. Peng T. Bucala R. Metz C.N. Peripheral blood fibrocytes: differentiation pathway and migration to wound sites.J Immunol. 2001; 166: 7556-7562Crossref PubMed Scopus (911) Google Scholar], fibrocytes also are found in stromal cultures of bone marrow, splenocytes, and solid organs [14Medbury H. Role of fibrocytes in atherogenesis.in: Bucala R. Fibrocytes: new insights into tissue repair and systemic fibroses. World Scientific Publishing Co. Pte. Ltd, Singapore2007: 175-194Crossref Scopus (4) Google Scholar]. In the normal host, fibrocytes constitute approximately 0.5% of circulating leukocytes [13Bucala R. Spiegel L.A. Chesney J. Hogan M. Cerami A. Circulating fibrocytes define a new leukocyte subpopulation that mediates tissue repair.Mol Med. 1994; 1: 71-81Crossref PubMed Google Scholar]. This quantity increases in response to certain cytokines and chemokines or the presence of underlying fibrotic or inflammatory conditions [16Mehrad B. Burdick M.D. Zisman D.A. Keane M.P. Belperio J.A. Strieter R.M. Circulating peripheral blood fibrocytes in human fibrotic interstitial lung disease.Biochem Biophys Res Commun. 2007; 353: 104-108Crossref PubMed Scopus (218) Google Scholar, 17Moeller A. Gilpin S.E. Ask K. et al.Circulating fibrocytes are an indicator for poor prognosis in idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 2009; 179: 588-594Crossref PubMed Scopus (418) Google Scholar]. Fibrocytes exit the circulation at sites of injury and contribute to the formation of granulomas, scars, and remodeled tissue [15Abe R. Donnelly S.C. Peng T. Bucala R. Metz C.N. Peripheral blood fibrocytes: differentiation pathway and migration to wound sites.J Immunol. 2001; 166: 7556-7562Crossref PubMed Scopus (911) Google Scholar].The coexpression of CD34 or CD45 with collagen-1 or pro-collagen−1 is considered sufficient to identify blood-borne fibrocytes in most settings [17Moeller A. Gilpin S.E. Ask K. et al.Circulating fibrocytes are an indicator for poor prognosis in idiopathic pulmonary fibrosis.Am J Respir Crit Care Med. 2009; 179: 588-594Crossref PubMed Scopus (418) Google Scholar]. Fibrocytes also produce the matrix components fibronectin and vimentin, and prolyl-hydroxylase has also been a useful marker in some studies [15Abe R. Donnelly S.C. Peng T. Bucala R. Metz C.N. Peripheral blood fibrocytes: differentiation pathway and migration to wound sites.J Immunol. 2001; 166: 7556-7562Crossref PubMed Scopus (911) Google Scholar, 18Pilling D. Fan T. Huang D. Kaul B. Gomer R.H. Identification of markers that distinguish monocyte-derived fibrocytes from monocytes, macrophages, and fibroblasts.PLoS One. 2009; 4: e7475Crossref PubMed Scopus (380) Google Scholar]. When used in conjunction with procollagen detection, leukocyte-specific protein-1, which is a p38 mitogen-activated protein kinase target, identifies fibrocytes in the post-burn hypertrophic scar [19Yang L. Scott P.G. Dodd C. et al.Identification of fibrocytes in postburn hypertrophic scar.Wound Repair Regen. 2005; 13: 398-404Crossref PubMed Scopus (146) Google Scholar]. Other hematopoietic markers expressed by these cells include CD11b, CD13, and major histocompatibility complex class II [15Abe R. Donnelly S.C. Peng T. Bucala R. Metz C.N. Peripheral blood fibrocytes: differentiation pathway and migration to wound sites.J Immunol. 2001; 166: 7556-7562Crossref PubMed Scopus (911) Google Scholar]. Fibrocytes lack lymphocyte markers such as CD3, CD4, CD8, CD19, and CD25 [13Bucala R. Spiegel L.A. Chesney J. Hogan M. Cerami A. Circulating fibrocytes define a new leukocyte subpopulation that mediates tissue repair.Mol Med. 1994; 1: 71-81Crossref PubMed Google Scholar].In a more recent study, the expression of CD45RO, 25F9 (a marker of mature macrophages), S100A8/A9 (calprotectin), and a lack of PM-2K (which identifies mature macrophages) identified fibrocytes in the lungs of patients with idiopathic pulmonary fibrosis (IPF) [18Pilling D. Fan T. Huang D. Kaul B. Gomer R.H. Identification of markers that distinguish monocyte-derived fibrocytes from monocytes, macrophages, and fibroblasts.PLoS One. 2009; 4: e7475Crossref PubMed Scopus (380) Google Scholar] both in vivo and after in vitro culture. The combination of CD34/CD45/pro-col-1 identified both fibrocytes and a subpopulation of macrophages; this may indicate a common progenitor population. Further work is needed to determine the differentiation pathway of fibrocytes from monocytic precursors. It is noteworthy that fibrocytes may share certain phenotypic features with alternatively activated macrophages, which are also considered to contribute to reparative processes [20Martinez F.O. Sica A. Mantovani A. Locati M. Macrophage activation and polarization.Front Biosci. 2008; 13: 453-461Crossref PubMed Scopus (2205) Google Scholar].Physiologic role in wound repairFibrocytes display many properties that are important for wound repair. Upon entry into diseased tissue, fibrocytes can adopt the phenotype of myofibroblasts as evidenced by the loss of CD34 and the acquisition of α−smooth muscle action (α-SMA) expression [15Abe R. Donnelly S.C. Peng T. Bucala R. Metz C.N. Peripheral blood fibrocytes: differentiation pathway and migration to wound sites.J Immunol. 2001; 166: 7556-7562Crossref PubMed Scopus (911) Google Scholar, 21Schmidt M. Sun G. Stacey M.A. Mori L. Mattoli S. Identification of circulating fibrocytes as precursors of bronchial myofibroblasts in asthma.J Immunol. 2003; 171: 380-389PubMed Google Scholar]; however, the extent to which this occurs in different settings of tissue repair remains unclear. Fibrocytes secrete proinflammatory cytokines (tumor necrosis factor, interleukin [IL]-6, IL-8, IL-10, macrophage inflammatory protein-1α/β and metalloproteinases, such as matrix metalloproteinase−9, in response to IL-1β stimulation [22Chesney J. Metz C. Stavitsky A.B. Bacher M. Bucala R. Regulated production of type I collagen and inflammatory cytokines by peripheral blood fibrocytes.J Immunol. 1998; 160: 419-425PubMed Google Scholar]. In addition, fibrocytes may demonstrate a proangiogeneic phenotype. They promote endothelial tube formation in vitro and neoangiogenesis within implanted Matrigel in vivo. Fibrocytes secrete the proangiogenic factors: vascular endothelial growth factor, platelet-derived growth factor−A, macrophage colony-stimulating factor, hepatocyte growth factor, granulocyte-macrophage colony-stimulating factor, basic fibroblast growth factor, and transforming growth factor (TGF), IL-8, and IL-1β [22Chesney J. Metz C. Stavitsky A.B. Bacher M. Bucala R. Regulated production of type I collagen and inflammatory cytokines by peripheral blood fibrocytes.J Immunol. 1998; 160: 419-425PubMed Google Scholar, 23Hartlapp I. Abe R. Saeed R.W. et al.Fibrocytes induce an angiogenic phenotype in cultured endothelial cells and promote angiogenesis in vivo.FASEB J. 2001; 15: 2215-2224Crossref PubMed Scopus (238) Google Scholar]. Fibrocytes also express a number of chemokine receptors that regulate the recruitment and trafficking of inflammatory cells. Lastly, fibrocytes express major histocompatibility complex class II and demonstrate antigen-presenting capabilities in vitro and in vivo [24Chesney J. Bacher M. Bender A. Bucala R. The peripheral blood fibrocyte is a potent antigen-presenting cell capable of priming naive T cells in situ.Proc Natl Acad Sci U S A. 1997; 94: 6307-6312Crossref PubMed Scopus (310) Google Scholar]. These functions may be expected to clearly influence the progression of wound healing and tissue remodeling responses. Further insight into fibrocyte function is provided by studies that have examined their differentiation, cell surface markers, and chemokine receptors.Fibrocyte differentiation and traffickingFibrocytes have been described to differentiate from a precursor population present within the CD14+ monocyte fraction of peripheral blood [15Abe R. Donnelly S.C. Peng T. Bucala R. Metz C.N. Peripheral blood fibrocytes: differentiation pathway and migration to wound sites.J Immunol. 2001; 166: 7556-7562Crossref PubMed Scopus (911) Google Scholar]. Further studies have determined that this precursor expresses the Fcγ receptor [25Pilling D. Buckley C.D. Salmon M. Gomer R.H. Inhibition of fibrocyte differentiation by serum amyloid P.J Immunol. 2003; 171: 5537-5546PubMed Google Scholar] and that inhibition of this receptor significantly reduces fibrocyte outgrowth. Fibrocyte differentiation from CD14+ precursors is augmented by the Th2 cytokines IL-4 and IL-13 and inhibited by the Th1 cytokines interferon-γ and IL-12 [26Shao D.D. Suresh R. Vakil V. Gomer R.H. Pilling D. Pivotal advance: Th-1 cytokines inhibit, and Th-2 cytokines promote fibrocyte differentiation.J Leukoc Biol. 2008; 83: 1323-1333Crossref PubMed Scopus (236) Google Scholar]. A very recent study indicates that fibrocytes differentiate from the CD11b(+) CD115(+) Gr1(+) cells within the CD14+ peripheral blood leukocyte fraction, and that activated T-cell subsets enhance fibrocyte outgrowth in culture [27Niedermeier M. Reich B. Rodriguez Gomez M. et al.CD4+ T cells control the differentiation of Gr1+ monocytes into fibrocytes.Proc Natl Acad Sci U S A. 2009; 106: 17892-17897Crossref PubMed Scopus (179) Google Scholar]. However, careful lineage-tracing studies will be required to confirm the monocyte origin of fibrocytes under different fibrogenic stimuli.Signaling pathways implicated in fibrocyte outgrowth include immunoreceptor tyrosine-based inhibition motifs, mammalian target of Rapamycin−phosphatidylinositol 3 kinase, and angiotensin receptor 2. Treatment of fibrocyte precursors with the Fc receptor antagonist serum amyloid P (SAP), with the mammalian target of Rapamycin inhibitor rapamycin [28Mehrad B. Burdick M.D. Strieter R.M. Fibrocyte CXCR4 regulation as a therapeutic target in pulmonary fibrosis.Int J Biochem Cell Biol. 2009; 41: 1708-1718Crossref PubMed Scopus (140) Google Scholar], or with the angiotensin receptor inhibitor valsartan [29Sakai N. Wada T. Matsushima K. et al.The renin-angiotensin system contributes to renal fibrosis through regulation of fibrocytes.J Hypertens. 2008; 26: 780-790Crossref PubMed Scopus (68) Google Scholar] attenuates fibrocyte accumulation in mouse models of fibrosis. Our own work indicates that the neuronal guidance protein and immunoregulatory surface molecule Semaphorin 7a critically regulates fibrocyte differentiation in a β1 integrin−dependent manner and that there is a requirement for apoptosis-derived signals in this process (Herzog et al., submitted). In these studies, genetic deletion of the glycosylphosphatidylinositol-anchored membrane protein Semaphorin 7a significantly attenuated intrapulmonary fibrocyte appearance in a TGFβ1 dependent mouse model of lung fibrosis. This effect was mimicked by disruption of β1 integrin function (a receptor for Semaphorin 7a expressed by fibrocytes) and by blocking apoptosis with the caspase inhibitor Z-VAD/fmk. Fibrocyte outgrowth also was observed to be increased threefold in a β1-integrin−dependent, caspase-dependent manner when human CD14+ cells were cultured in the presence of recombinant Semaphorin 7a.It has been postulated that the ultimate phenotype of fibrocytes is the contractile myofibroblast [15Abe R. Donnelly S.C. Peng T. Bucala R. Metz C.N. Peripheral blood fibrocytes: differentiation pathway and migration to wound sites.J Immunol. 2001; 166: 7556-7562Crossref PubMed Scopus (911) Google Scholar, 30Phillips R.J. Burdick M.D. Hong K. et al.Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis.J Clin Invest. 2004; 114: 438-446Crossref PubMed Scopus (912) Google Scholar, 31Quan T.E. Cowper S. Wu S.P. Bockenstedt L.K. Bucala R. Circulating fibrocytes: collagen-secreting cells of the peripheral blood.Int J Biochem Cell Biol. 2004; 36: 598-606Crossref PubMed Scopus (487) Google Scholar, 32Gomperts B.N. Strieter R.M. Fibrocytes in lung disease.J Leukoc Biol. 2007; 82: 449-456Crossref PubMed Scopus (127) Google Scholar]. This idea is based on the finding that cultured fibrocytes respond to TGFβ1 by expressing α-SMA and contracting collagen gels in vitro [15Abe R. Donnelly S.C. Peng T. Bucala R. Metz C.N. Peripheral blood fibrocytes: differentiation pathway and migration to wound sites.J Immunol. 2001; 166: 7556-7562Crossref PubMed Scopus (911) Google Scholar, 30Phillips R.J. Burdick M.D. Hong K. et al.Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis.J Clin Invest. 2004; 114: 438-446Crossref PubMed Scopus (912) Google Scholar, 31Quan T.E. Cowper S. Wu S.P. Bockenstedt L.K. Bucala R. Circulating fibrocytes: collagen-secreting cells of the peripheral blood.Int J Biochem Cell Biol. 2004; 36: 598-606Crossref PubMed Scopus (487) Google Scholar, 32Gomperts B.N. Strieter R.M. Fibrocytes in lung disease.J Leukoc Biol. 2007; 82: 449-456Crossref PubMed Scopus (127) Google Scholar]. However, the ability of fibrocytes to differentiate into myofibroblasts in vivo is less clear. Studies using bone marrow transplantation show only a minimal contribution of fibrocytes to α-SMA production in some models [33Lin S.L. Kisseleva T. Brenner D.A. Duffield J.S. Pericytes and perivascular fibroblasts are the primary source of collagen-producing cells in obstructive fibrosis of the kidney.Am J Pathol. 2008; 173: 1617-1627Abstract Full Text Full Text PDF PubMed Scopus (647) Google Scholar, 34Kisseleva T. Uchinami H. Feirt N. et al.Bone marrow-derived fibrocytes participate in pathogenesis of liver fibrosis.J Hepatol. 2006; 45: 429-438Abstract Full Text Full Text PDF PubMed Scopus (396) Google Scholar, 35Hashimoto N. Jin H. Liu T. Chensue S.W. Phan S.H. Bone marrow derived progenitor cells in pulmonary fibrosis.J Clin Invest. 2004; 113: 243-252Crossref PubMed Scopus (643) Google Scholar], implying that this differentiation pathway may not necessarily be a dominant feature of fibrocytes in the tissue remodeling response.Fibrocyte recruitment into tissuesMurine fibrocytes express the chemokine receptors CCR2, CCR7, and CXCR4; these molecules mediate the recruitment of fibrocytes to injured tissue [30Phillips R.J. Burdick M.D. Hong K. et al.Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis.J Clin Invest. 2004; 114: 438-446Crossref PubMed Scopus (912) Google Scholar, 36Moore B.B. Murray L. Das A. Wilke C.A. Herrygers A.B. Toews G.B. The role of CCL12 in the recruitment of fibrocytes and lung fibrosis.Am J Respir Cell Mol Biol. 2006; 35: 175-181Crossref PubMed Scopus (250) Google Scholar, 37Sakai N. Wada T. Yokoyama H. et al.Secondary lymphoid tissue chemokine (SLC/CCL21)/CCR7 signaling regulates fibrocytes in renal fibrosis.Proc Natl Acad Sci U S A. 2006; 103: 14098-14103Crossref PubMed Scopus (220) Google Scholar]. Human fibrocytes also express the chemokine receptors CCR3 (eotaxin receptor) and CCR5 (monocyte chemoattractant protein-1 [MCP-1] receptor) [31Quan T.E. Cowper S. Wu S.P. Bockenstedt L.K. Bucala R. Circulating fibrocytes: collagen-secreting cells of the peripheral blood.Int J Biochem Cell Biol. 2004; 36: 598-606Crossref PubMed Scopus (487) Google Scholar]. While there are only limited data regarding the circulating mediators that effect fibrocyte recruitment in humans, our own work demonstrates an association between circulating concentrations of MCP-1 and high levels of CD45/Pro-Col-1+ve fibrocytes in the circulation of scleroderma patients with interstitial lung disease ILD) or in healthy aging (S. Mathai, submitted). These data suggest that MCP-1 may be involved in mobilization of fibrocytes into the peripheral blood. In addition, high levels of CXCL12, which is the ligand for CXCR4, have been found in the lungs and blood of patients with IPF and these levels correlate with circulating fibrocyte concentrations [16Mehrad B. Burdick M.D. Zisman D.A. Keane M.P. Belperio J.A. Strieter R.M. Circulating peripheral blood fibrocytes in human fibrotic interstitial lung disease.Biochem Biophys Res Commun. 2007; 353: 104-108Crossref PubMed Scopus (218) Google Scholar]. Nevertheless, the relationship between chemokine production and fibrocyte differentiation and trafficking is an active area of investigation with the potential to lead to new therapies for fibrosing diseases.Role in pathologic disorders and fibrosing diseasesFibrocytes in lung diseaseFibrotic lung disease can affect the airway (asthma) and the parenchyma (pulmonary fibrosis). In both of these disorders, the progressive destruction of normal lung tissue leads to lung remodeling and persistent gas exchange abnormalities. Fibrocytes have been implicated in the pathogenesis of both asthma and pulmonary fibrosis.AsthmaThe lungs of patients with chronic asthma demonstrate persistent inflammation and remodeling of the airways. The latter leads to progressive airway obstruction and a permanent impairment in respiratory function. Pathologic examination of these tissues demonstrate subepithelial fibrosis and myofibroblast accumulation. A number of studies have demonstrated fibrocytes in these lesions [21Schmidt M. Sun G. Stacey M.A. Mori L. Mattoli S. Identification of circulating fibrocytes as precursors of bronchial myofibroblasts in asthma.J Immunol. 2003; 171: 380-389PubMed Google Scholar, 38Wang C.H. Huang C.D. Lin H.C. et al.Increased circulating fibrocytes in asthma with chronic airflow obstruction.Am J Respir Crit Care Med. 2008; 178: 583-591Crossref PubMed Scopus (147) Google Scholar]. The first evidence for fibrocytes in asthma came in 2003 when Schmidt et al. [21Schmidt M. Sun G. Stacey M.A. Mori L. Mattoli S. Identification of circulating fibrocytes as precursors of bronchial myofibroblasts in asthma.J Immunol. 2003; 171: 380-389PubMed Google Scholar] demonstrated that the airways of patients with asthma contained fibrocytes (characterized by CD34/procollagen-1a expression) and that these cells increased in number following allergen exposure. Concurrent studies in a mouse model of antigen-induced asthma demonstrated that circulating fibrocytes trafficked to the lungs of aerosolized antigen-challenged mice. Once in the lungs, fibrocytes quickly lost CD34 expression and acquired expression of α-SMA, which is consistent with the differentiation of these cells into myofibroblasts [21Schmidt M. Sun G. Stacey M.A. Mori L. Mattoli S. Identification of circulating fibrocytes as precursors of bronchial myofibroblasts in asthma.J Immunol. 2003; 171: 380-389PubMed Google Scholar]. Subsequent studies have found that CD34+/45+α-SMA+ cells recovered from the bronchoalveolar lavage fluid of patients with asthma display characteristics of fibrocytes; moreover, the presence of fibrocytes correlated with airway basement membrane thickness on histologic sections [39Nihlberg K. Larsen K. Hultgårdh-Nilsson A. Malmström A. Bjermer L. Westergren-Thorsson G. Tissue fibrocytes in patients with mild asthma: a possible link to thickness of reticular basement membrane?.Respir Res. 2006; 7: 50Crossref PubMed Scopus (117) Google Scholar]. Circulating fibrocytes also may be associated with chronic asthma; in one study patients with chronic persistent asthma showed an increase in circulating fibrocytes enumerated by in vitro culture [39Nihlberg K. Larsen K. Hultgårdh-Nilsson A. Malmström A. Bjermer L. Westergren-Thorsson G. Tissue fibrocytes in patients with mild asthma: a possible link to thickness of reticular basement membrane?.Respir Res. 2006; 7: 50Crossref PubMed Scopus (117) Google Scholar]. Interestingly, the presence of increased numbers of circulating fibrocytes displayed a positive correlation with the rate of forced expiratory volume in 1 second decline. The appearance of fibrocytes in the culture of asthmatic peripheral blood mononuclear cells was attenuated by the addition of normal serum [38Wang C.H. Huang C.D. Lin H.C. et al.Increased circulating fibrocytes in asthma with chronic airflow obstruction.Am J Respir Crit Care Med. 2008; 178: 583-591Crossref PubMed Scopus (147) Google Scholar], thus implying that serum factors are responsible, at least in part, for the increased number of fibrocytes in the circulation of asthma patients. Increased concentrations of fibrocytes also have been detected by direct measurement of these cells in the lungs and the blood of patients with severe chronic asthma [40Saunders R. Siddiqui S. Kaur D. et al.Fibrocyte localization to the airway smooth muscle is a feature of asthma.J Allergy Clin Immunol. 2009; 123: 376-384Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar].Pulmonary fibrosisThe term pulmonary fibrosis encompasses a heterogeneous group of disorders characterized by progressive replacement of the lung parenchyma with collagen and ECM components. The most common form of the disease, IPF, differs from most other types of the disease in both its lack of known etiology and unresponsiveness to therapy.Intrapulmonary fibrocytes have been detected in several experimental models of lung fibrosis [9Pereira R.F. Halford K.W. O'Hara M.D. et al.Cultured adherent cells from marrow can serve as long-lasting precursor c