Abstract
A single early-phase infusion of apoptotic cells can inhibit bleomycin-induced lung inflammation and fibrosis; however, it is unknown whether these effects can be enhanced with additional infusions and/or statin treatment. Here, we investigated whether an increased frequency of apoptotic cell injection, with or without efferocytosis enhancer simvastatin, facilitates therapeutic efficacy. An additional injection of apoptotic cells during the intermediate phase (7 days post-bleomycin treatment) or simvastatin administration alone on days 7–13 post-treatment did not promote anti-fibrotic responses beyond those induced by a single early apoptotic cell infusion alone. Additional administration of apoptotic cells with simvastatin further enhanced the efferocytic ability of alveolar macrophages and PPARγ activity, and induced hepatocyte growth factor and interleukin-10 expression, in alveolar macrophages and lung tissue. Additional administration of apoptotic cells with simvastatin also reduced mRNA expression of bleomycin-induced epithelial-mesenchymal transition (EMT) markers in isolated alveolar type II epithelial cells, fibrotic markers in fibroblasts, and hydroxyproline in lung tissue. Enhanced anti-EMT and anti-fibrotic efficacy was confirmed by immunofluorescence and trichrome staining of lung tissue. This suggests that additional administration of apoptotic cells with simvastatin during the intermediate phase of bleomycin-induced lung fibrosis may boost the anti-fibrotic properties of early apoptotic cell infusion.
Highlights
Pulmonary fibrosis is a potentially fatal disease, characterized by continuous alveolar epithelial injury and dysregulated repair, leading to myofibroblast accumulation and excessive deposition of extracellular matrix and connective tissue
We observed that an additional apoptotic cell infusion, or simvastatin treatment alone (BLM+twice Apo and BLM+single Apo+Simv, respectively) 7 days post-bleomycin treatment did not enhance phagocytic indices in alveolar macrophages 2 h after infusion, when compared to a single early apoptotic cell infusion (BLM+single Apo; Figures 1b and c)
We examined whether an increased frequency of apoptotic cell injection, with or without simvastatin enhances PPARγ expression and its activity in alveolar macrophages and lung tissue
Summary
Pulmonary fibrosis is a potentially fatal disease, characterized by continuous alveolar epithelial injury and dysregulated repair, leading to myofibroblast accumulation and excessive deposition of extracellular matrix and connective tissue. Administration of apoptotic cells has been shown to attenuate LPS-induced acute lung injury or sepsis.[2,3,4] apoptotic cell injection has been used to reduce the chronic phases of inflammatory arthritis,[5] insulitis in mouse type 1 diabetes,[6] and autoimmune inflammation.[7] These beneficial effects have been attributed to the release of anti-inflammatory cytokines, such as transforming growth factor (TGF)-β and interleukin (IL)-10, by macrophages upon apoptotic cell recognition and clearance. Morimoto and colleagues demonstrated that lovastatin enhances clearance of apoptotic cells in the naive murine lung and ex vivo in alveolar macrophages from chronic obstructive pulmonary disease.[13] Statins display antiinflammatory and anti-fibrotic effects in acute lung injury,[14] bleomycin-induced pulmonary fibrosis,[15] and inflammatory. The additional injection of apoptotic cells with a simvastatin regimen boosts the anti-epithelial–mesenchymal transition (EMT) and anti-fibrotic responses induced by early apoptotic cell infusion
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