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Significance Liver resident activated hepatic stellate cells (aHSCs), and activated portal fibroblasts (aPFs) are the major source of the fibrous scar in the liver. aPFs have been implicated in liver fibrosis caused by cholestatic liver injury, whereas fibrosis in hepatotoxic liver injury is attributed to aHSCs. However, the contribution of aPFs to cholestatic fibrosis is not well characterized because of difficulties in cell purification and the lack of identified aPF-specific markers. We have developed a novel flow cytometry-based method of aPFs purification from the nonparenchymal cell fraction of collagen-α1(I)-GFP mice and have identified potential aPF-specific markers. The goal of this study is to determine whether aPFs contribute to cholestatic liver fibrosis and identify the mechanism(s) of their activation.

TGF-beta1 induces EMT in a Smad3-dependent manner in primary AECs. However, in asthmatic-derived ALI-AEC cultures, the number of cells undergoing EMT is greater. These findings support the hypothesis that epithelial repair in asthmatic airways is dysregulated.

We have previously shown that mice that are genetically deficient in the CCR2 gene (CCR2؊/؊ mice) are protected from fluorescein isothiocyanate (FITC)-induced lung fibrosis. Protection from fibrosis correlated with impaired recruitment of fibrocytes (bone marrowderived cells, which share both leukocyte and mesenchymal markers). There are three ligands for CCR2 in the mouse: CCL2, CCL7, and CCL12. CCL2 and CCL12 are both elevated in the lung after FITC injury, but with different kinetics. CCL2 is maximal at Day 1 and absent by Day 7 after FITC. In contrast, CCL12 peaks at Day 3, but remains elevated through Day 21 after FITC. We now demonstrate that while CCR2؊/؊ mice are protected from FITC-induced fibrosis, CCL2؊/؊ mice are not. CCL2؊/؊ mice are able to recruit fibrocytes to FITC-injured airspaces, unlike CCR2؊/؊ mice. Adoptive transfer of CCR2-expressing fibrocytes augments FITC-induced fibrosis in both wild-type and CCR2؊/؊ mice, suggesting that these cells play a pathogenic role in the disease process. Both CCL2 and CCL12 are chemotactic for fibrocytes. However, neutralization of CCL12 in wild-type mice significantly protects from FITC-induced fibrosis, whereas neutralization of CCL2 was less effective. Thus, CCL12 is likely the CCR2 ligand responsible for driving fibroproliferation in the mouse. As murine CCL12 is homologous to human CCL2, we suggest that the pathobiology of murine CCL12 in fibroproliferation may correlate to human CCL2 biology.