Abstract
Type II alveolar epithelial cell (AEC) apoptosis is a prominent feature of fibrotic lung diseases and animal models of pulmonary fibrosis. While there is growing recognition of the importance of AEC injury and apoptosis as a causal factor in fibrosis, the underlying mechanisms that link these processes remain unknown. We have previously shown that targeting the type II alveolar epithelium for injury by repetitively administering diphtheria toxin to transgenic mice expressing the diphtheria toxin receptor off of the surfactant protein C promoter (SPC-DTR) develop lung fibrosis, confirming that AEC injury is sufficient to cause fibrosis. In the present study, we find that SPC-DTR mice develop increased activation of caspase 3/7 after initiation of diphtheria toxin treatment consistent with apoptosis within AECs. We also find evidence of efferocytosis, the uptake of apoptotic cells, by alveolar macrophages in this model. To determine the importance of efferocytosis in lung fibrosis, we treated cultured alveolar macrophages with apoptotic type II AECs and found that the uptake induced pro-fibrotic gene expression. We also found that the repetitive intrapulmonary administration of apoptotic type II AEC or MLE-12 cells induces lung fibrosis. Finally, mice lacking a key efferocytosis receptor, CD36, developed attenuated fibrosis in response to apoptotic MLE-12 cells. Collectively, these studies support a novel mechanism linking AEC apoptosis with macrophage pro-fibrotic activation via efferocytosis and reveal previously unrecognized therapeutic targets.
Highlights
Progressive alveolar fibrosis is a serious complication of certain systemic inflammatory disorders, inorganic and organic dust exposures, drug toxicity and primary diseases of the lung including idiopathic pulmonary fibrosis (IPF)[1,2,3,4,5]
Increased lung apoptosis following targeted type II alveolar epithelial cell injury We have previously described the generation of transgenic mice (SPC-DDTR) in which the murine surfactant promoter C promoter drives diphtheria toxin receptor expression in a type II AEC-specific manner[11]
We found that DT treatment resulted in a marked increase in caspase 3/7 activity in SPC-DTR mice (Fig. 1a) and transferase dUTP-mediated nick-end labeling (TUNEL)-staining within pro-SPCpositve cells (Supplemental Fig. 1), confirming that the targeted insult leads to increased apoptotic cell death
Summary
Progressive alveolar fibrosis is a serious complication of certain systemic inflammatory disorders, inorganic and organic dust exposures, drug toxicity and primary diseases of the lung including idiopathic pulmonary fibrosis (IPF)[1,2,3,4,5]. Mounting evidence implicates defects in the type II alveolar epithelial cell (AEC) in disease pathogenesis[6]. Histopathologic abnormalities of the epithelium including apoptosis are observed in tissue sections from IPF patients and in animal models of pulmonary fibrosis[7,8,9]. Despite the substantial evidence linking type II AEC injury/death to the development of fibrosis, the pathways that translate an epithelial insult into lung collagen accumulation have not been well-characterized. An alternative mechanism supported by emerging evidence suggests that the apoptotic AECs can directly trigger progressive fibrosis by inducing a response in neighboring cells
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