Targeted injury of type II alveolar epithelial cells induces pulmonary fibrosis.

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical Center, 1150 West Medical Center Drive, 6301 MSRB III, Ann Arbor, MI 48109-5642, USA.
American Journal of Respiratory and Critical Care Medicine (Impact Factor: 11.04). 10/2009; 181(3):254-63. DOI: 10.1164/rccm.200810-1615OC
Source: PubMed

ABSTRACT Ineffective repair of a damaged alveolar epithelium has been postulated to cause pulmonary fibrosis. In support of this theory, epithelial cell abnormalities, including hyperplasia, apoptosis, and persistent denudation of the alveolar basement membrane, are found in the lungs of humans with idiopathic pulmonary fibrosis and in animal models of fibrotic lung disease. Furthermore, mutations in genes that affect regenerative capacity or that cause injury/apoptosis of type II alveolar epithelial cells have been identified in familial forms of pulmonary fibrosis. Although these findings are compelling, there are no studies that demonstrate a direct role for the alveolar epithelium or, more specifically, type II cells in the scarring process.
To determine if a targeted injury to type II cells would result in pulmonary fibrosis.
A transgenic mouse was generated to express the human diphtheria toxin receptor on type II alveolar epithelial cells. Diphtheria toxin was administered to these animals to specifically target the type II epithelium for injury. Lung fibrosis was assessed by histology and hydroxyproline measurement.
Transgenic mice treated with diphtheria toxin developed an approximately twofold increase in their lung hydroxyproline content on Days 21 and 28 after diphtheria toxin treatment. The fibrosis developed in conjunction with type II cell injury. Histological evaluation revealed diffuse collagen deposition with patchy areas of more confluent scarring and associated alveolar contraction.
The development of lung fibrosis in the setting of type II cell injury in our model provides evidence for a causal link between the epithelial defects seen in idiopathic pulmonary fibrosis and the corresponding areas of scarring.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Apoptosis of type II alveolar epithelial cells (AECs-II) is a key determinant of initiation and progression of lung fibrosis. However, the mechanism of miR-30a participation in the regulation of AECs-II apoptosis is ambiguous. In this study, we investigated whether miR-30a could block AECs-II apoptosis by repressing mitochondrial fission dependent on dynamin-related protein-1 (Drp-1). The levels of miR-30a in vivo and in vitro were determined through quantitative real-time PCR (qRT-PCR). The inhibition of miR-30a in AECs-II apoptosis, mitochondrial fission and its dependence on Drp-1, and Drp-1 expression and translocation were detected using miR-30a mimic, inhibitor-transfection method (gain- and loss-of-function), or Drp-1 siRNA technology. Results showed that miR-30a decreased in lung fibrosis. Gain- and loss-of-function studies revealed that the up-regulation of miR-30a could decrease AECs-II apoptosis, inhibit mitochondrial fission, and reduce Drp-1 expression and translocation. MiR-30a mimic/inhibitor and Drp-1 siRNA co-transfection showed that miR-30a could inhibit the mitochondrial fission dependent on Drp-1. This study demonstrated that miR-30a inhibited AECs-II apoptosis by repressing the mitochondrial fission dependent on Drp-1, and could function as a novel therapeutic target for lung fibrosis.
    Journal of Cellular and Molecular Medicine 10/2014; · 3.70 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Pulmonary fibrosis is an irreversible chronic progressive fibroproliferative lung disease, which usually has a poor prognosis. Previous studies have confirmed that the transplantation of bone marrow mesenchymal stem cells (MSCs) significantly reduces lung damage in a number of animal models. However, the underlying mechanism involved in this process remains to be elucidated. In the present study, a bleomycin (BLM)‑induced female Wister rat model of fibrosis was established. At 0 or 7 days following BLM administration, rats were injected into the tail vein with 5‑bromo‑2‑deoxyuridine‑labeled MSCs extracted from male Wistar rats. The lung tissue of the rats injected with MSCs expressed the sex‑determining region Y gene. The level surfactant protein C (SP‑C), a marker for type II alveolar epithelial cells (AEC II), was higher in the group injected with MSCs at day 0 than that in the group injected at day 7. Furthermore, SP‑C mRNA, but not aquaporin 5 mRNA, a marker for type I alveolar epithelial cells, was expressed in fresh bone marrow aspirates and the fifth generation of cultured MSCs. In addition, superoxide dismutase activity and total antioxidative capability, specific indicators of oxidative stress, were significantly increased in the lung tissue of the MSC‑transplanted rats (P<0.05). In conclusion, to alleviate pulmonary fibrosis, exogenous MSCs may be transplanted into damaged lung tissue where they differentiate into AEC II and exert their effect, at least in part, through blocking oxidative stress.
    Molecular Medicine Reports 11/2014; · 1.48 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The chronic debilitating lung disease idiopathic pulmonary fibrosis (IPF) is characterized by a progressive decline in lung function, with a median mortality rate of 2-3 years after diagnosis. IPF is a disease of unknown cause and progression, and multiple pathways have been demonstrated to be activated in the lungs of these patients. A recent genome-wide association study of more than a thousand IPF patients identified genes linked to host defence, cell-cell adhesion, and DNA repair being altered due to fibrosis(1). Further emerging data suggests that the respiratory system may not be a truly sterile environment, and it exhibits an altered microbiome during fibrotic disease(2). These altered host defence mechanisms might explain the increased susceptibility of IPF patients to microbial- and viral-induced exacerbations. Moreover, chronic epithelial injury and apoptosis are key features in IPF, which might be mediated, in part, by both pathogen-associated (PA) and danger-associated (DA) molecular patterns (MPs). Emerging data indicate that both PAMPs and DAMPs contribute to apoptosis but not necessarily in a manner that allows for the removal of dying cells, without further exacerbating inflammation. In contrast, both types of MPs drive cellular necrosis leading to an exacerbation of lung injury and/or infection as the debris promotes a pro-inflammatory response. Thus, this review will focus on the impact of MPs resulting from infection-driven apoptosis and necrosis during chronic fibrotic lung disease.
    American Journal of Respiratory Cell and Molecular Biology 04/2014; · 4.15 Impact Factor