Central to the formation of fibrotic lesions are the accumulation of fibroblasts and extracellular matrix. The origin of fibroblasts in lung fibrosis has been the subject of numerous studies. Current evidence suggests multiple sources which may vary with the type of injury or inciting events including proliferation of resident lung fibroblasts, differentiation of progenitor cells from the bone marrow, and transition of epithelial cells to a fibroblast phenotype, termed epithelial-mesenchymal transition (EMT). Bone marrow derived circulating fibroblast precursors are called fibrocytes.10
Fibrocytes have been shown to be a component of hypertrophic scars and keloids,11
scleroderma, kidney lesions,12
thickened airways caused by asthma13,14
and lung fibrosis15
in certain experimental models. Fibrocytes, defined by co-expression of CXCR4, a fibrocyte-associated chemokine receptor, procollagen I, α-SMA and prolyl-4-hydroxylase, were identified in lung tissue of 8/9 pulmonary fibrosis patients16
supporting a role of fibrocytes in human disease. A positive correlation of fibroblastic foci and lung fibrocytes (r = 0.79; p < 0.02) was shown but the extent of fibrocyte recruitment in multiple forms of pulmonary fibrosis is not known. The precise role of fibrocytes remains controversial because although cultured fibrocytes can be induced to differentiate into myofibroblasts in vitro, it is not clear that fibrocytes contribute to pathologic fibrosis in vivo.15,17,18
In the setting of fibrogenic injury, bone-marrow derived mesenchymal stem cells may actually be promoting repair and ameliorating fibrosis rather that causing persistent fibrotic lesions.19
Conflicting results using different stem cell pools and different animal models (reviewed in ref. 20
) indicate that the role of fibrocytes is not resolved.
Another possible pathological source of lung fibroblasts is EMT. EMT is known to occur during embryogenesis and organogenesis. In some forms of metastatic epithelial-based malignancies, epithelial and mesenchymal cells undergo EMT.21
Primary human and rat alveolar epithelial cells and human bronchial and distal airspace epithelial cell lines can be induced to undergo EMT.22,23
Bleomycin lung injury and transgenic mice with TGFβ overexpression in the lung cause pulmonary fibrosis. In both models upregulation of mesenchymal markers, α-SMA and vimentin, were detected in cells co-expressing E-cadherin and surfactant protein-C (SP-C), which are markers of epithelial cells.23,24
Other studies have demonstrated colocalization of epithelial markers, such as thyroid transcription factor-1 or pro-surfactant protein B or C, with mesenchymal markers, α-SMA or N-cadherin in cells overlying fibroblastic foci in IPF.24,25
The precise role of EMT remains controversial because other studies have failed to detect dual expression of epithelial and mesenchymal markers in vivo in either clinical samples or the bleomycin model.26
Considered together, fibrocytes, EMT and activation of resident lung fibroblasts may contribute to lung fibrosis but the precise role for each process in disease burden remains unresolved. Understanding the relative contribution of these processes and the specific forms of fibrosis to which each process contributes is important, as there may be different pathways regulating these processes suggesting different targets for potential therapy.