Targeted injury of type II alveolar epithelial cells induces pulmonary fibrosis.
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.
[Show abstract] [Hide abstract]
ABSTRACT: Fibrotic disorders account for an increasing burden of disease-associated morbidity and mortality worldwide. Although numerous risk factors have been recognized, the etiologies of many of these clinical syndromes have not been identified, and they are often termed idiopathic or cryptogenic. Here, we provide an evolutionary perspective on fibrosis aimed at elucidating its etiopathogenesis. By asking the ultimate question of "why" this process evolved in multicellular organisms, we hope to uncover proximate explanations for "how" it causes disease in humans. We posit that physiological fibrosis-like reactions evolved as an essential process in host defense against pathogens and in normal wound healing. Based on this premise, we reason that pathological fibrosis is related to one or more of the following: unidentified infectious or noninfectious antigens, autoimmunity, impaired regenerative responses, and the antagonistically pleiotropic action of genes involved in wound healing or development. The importance of genetic susceptibility, epigenetics, aging, and the modern-day environment are highlighted. Consideration of both ultimate and proximate causation goes beyond philosophical cogitations, as it will better inform pathobiological mechanisms of disease and aid in the prevention and treatment of fibrotic diseases.Journal of Clinical Investigation 11/2014; 124(11):4673-7. DOI:10.1172/JCI74368 · 13.77 Impact Factor
[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; 11(3). DOI:10.3892/mmr.2014.2981 · 1.48 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Recruitment of peripheral monocytes to the liver is a key contributor to the response to injury. MIF can act as a chemokine and cytokine, regulating innate immune responses in many tissues and cell types. We hypothesized that MIF contributes to the progression of CCl4-induced hepatic fibrosis by regulating recruitment of SAM. SAMs dynamically regulate HSC activation and ECM degradation. To gain insight into the role of MIF in progression of liver fibrosis, we investigated markers of fibrosis and immune responses after chronic CCl4 administration to female C57BL/6 and MIF(-/-) mice. Chronic CCl4 exposure increased activation of HSC in WT mice, indicated by increased expression of αSMA mRNA and protein, as well as mRNA for collagen 1α1; these responses were blunted in female MIF(-/-) mice. Despite lower activation of HSC in MIF(-/-) mice, accumulation of ECM was similar in WT and MIF(-/-)mice, suggesting a decreased rate of ECM degradation. Recruitment of SAMs was lower in MIF(-/-) mice compared with WT mice, both in their initial inflammatory phenotype, as well as in the later phase as proresolution macrophages. The decreased presence of resolution macrophages was associated with lower expression of MMP13 in MIF(-/-) mice. Taken together, these data indicate that MIF-dependent recruitment of SAMs contributes to degradation of ECM via MMP13, highlighting the importance of appropriate recruitment and phenotypic profile of macrophages in the resolution of fibrosis.Journal of Leukocyte Biology 11/2014; 97(1). DOI:10.1189/jlb.3A0614-280R · 4.30 Impact Factor