Abstract
The potential for amniotic fluid stem cell (AFSC) treatment to inhibit the progression of fibrotic lung injury has not been described. We have previously demonstrated that AFSC can attenuate both acute and chronic-fibrotic kidney injury through modification of the cytokine environment. Fibrotic lung injury, such as in Idiopathic Pulmonary Fibrosis (IPF), is mediated through pro-fibrotic and pro-inflammatory cytokine activity. Thus, we hypothesized that AFSC treatment might inhibit the progression of bleomycin-induced pulmonary fibrosis through cytokine modulation. In particular, we aimed to investigate the effect of AFSC treatment on the modulation of the pro-fibrotic cytokine CCL2, which is increased in human IPF patients and is correlated with poor prognoses, advanced disease states and worse fibrotic outcomes. The impacts of intravenous murine AFSC given at acute (day 0) or chronic (day 14) intervention time-points after bleomycin injury were analyzed at either day 3 or day 28 post-injury. Murine AFSC treatment at either day 0 or day 14 post-bleomycin injury significantly inhibited collagen deposition and preserved pulmonary function. CCL2 expression increased in bleomycin-injured bronchoalveolar lavage (BAL), but significantly decreased following AFSC treatment at either day 0 or at day 14. AFSC were observed to localize within fibrotic lesions in the lung, showing preferential targeting of AFSC to the area of fibrosis. We also observed that MMP-2 was transiently increased in BAL following AFSC treatment. Increased MMP-2 activity was further associated with cleavage of CCL2, rendering it a putative antagonist for CCL2/CCR2 signaling, which we surmise is a potential mechanism for CCL2 reduction in BAL following AFSC treatment. Based on this data, we concluded that AFSC have the potential to inhibit the development or progression of fibrosis in a bleomycin injury model during both acute and chronic remodeling events.
Highlights
Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive and fatal lung disease, surmised to result from a myriad of factors
Since we previously demonstrated that amniotic fluid stem cell (AFSC) treatment most significantly attenuates CCL2 secreted into the bronchoalveolar lavage (BAL) following bleomycin injury (Figure 3, A–D), Western blots of cell fractions were not used to measure changes in levels of CCL2 secretion, but instead as an indicator of the presence and type of CCL2
The bleomycin injury model falls short as a perfect model for human idiopathic pulmonary fibrosis, certain aspects, which have been characterized in the literature and in the data presented, serve as useful facsimile for human IPF [46,48,49]
Summary
IPF is a chronic, progressive and fatal lung disease, surmised to result from a myriad of factors. At the cellular level IPF is characterized by alveolar epithelial injury, the initiation of inflammatory cascades, exaggerated pro-fibrotic cytokine expression, increased extracellular matrix deposition, and the development of fibrotic lesions termed ‘foci’ [2,3,4,5]. Expression of the pro-fibrotic cytokine CCL2 plays a significant role in IPF as previous studies indicate that it is primarily secreted by type II alveolar epithelia (AECII) and its secretion is significantly increased during inflammatory and fibrotic remodeling events in the lung [7,8,9,10,11]. In experimental models of lung fibrosis, increased expression of CCL2 attracts fibroblasts, and stimulates their collagen secretion and proliferation [12,13,14]. Emerges the importance of CCL2/CCR2 signaling in the pathogenesis of pulmonary fibrosis
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