Therapies for bleomycin induced lung fibrosis through regulation of TGF‐β1 induced collagen gene expression

Abstract

This review describes normal and abnormal wound healing, the latter characterized by excessive fibrosis and scarring, which for lung can result in morbidity and sometimes mortality. The cells, the extracellular matrix (ECM) proteins, and the growth factors regulating the synthesis, degradation, and deposition of the ECM proteins will be discussed. Therapeutics with particular emphasis given to gene therapies and their effects on specific signaling pathways are described. Bleomycin (BM), a potent antineoplastic antibiotic increases TGFb1 transcription, TGF-b1 gene expression, and TGF-b protein. Like TGF-b1, BM acts through the same distal promoter cis-element of the COL1A1 gene causing increased COL1 synthesis and lung fibrosis. Lung fibroblasts exist as subpopulations with one subset predominately responding to fibrogenic stimuli which could be a specific cell therapeutic target for the onset and development of pulmonary fibrosis.J TGF-b1 is an important modulator in the acute repair phase of a wound. It is a profibrotic factor that affects many cellular functions, including fibroblast proliferation and chemotaxis, stimulating the synthesis and deposition of connective tissue, and the inhibition of connective tissue breakdown. Type I collagen (COL 1) is the major fibrous collagen synthesized by wound fibroblasts in the repair process. When levels of TGF-b1 are chronically elevated, excessive fibrosis results which is characterized by increased collagen deposition. Fibrosis is the response to a traumatic event which terminates in the deposition of a connective tissue matrix. The composition and volume of that matrix differentiates between normal scar in acute wound repair and excessive fibrosis from chronic inflammation. In general, excess fibrosis contains increased concentrations of collagen, a rich blood supply, and myofibroblasts, identified by a-smooth muscle (SM) actin in cytoplasmic stress fibers. The development of fibrosis follows the sequence of overlapping phases; lag, proliferative, and remodeling. Either prolonging the proliferative phase and/or hindering the remodeling phase causes excess fibrosis. Trauma initiates the repair process that can terminate in a normal flat scar or a raised hypertrophic scar. The acute wound repair process provides a rapid and efficient way to restore mechanical tissue integrity. On the other hand, excess fibrosis is a prolonged process that can terminate into functional morbidity. An early event in repair is the restoration of homeostasis by the deposition of a fibrin clot which forms the highway for the migration of cells into the defect. At the termination of fibrosis, the fibrin matrix is replaced with a collagen matrix. The initial cells to travel the fibrin highway are the inflammatory cells. First, neutrophils enter the wound site followed by macrophages. Inflammatory cells prevent microbial colonization, remove dead tissue, and release factors that promote the proliferative phase. Fibroblasts and endothelial cells migrate into the wound site, where they synthesiz...

MiR-21 Mediates Fibrogenic Activation Of Pulmonary Fibroblasts And Lung Fibrosis

“…miR-21 has previously been shown to be induced in TGF-1-treated human vascular smooth muscle cells and to regulate the expression of genes involved in the contraction of smooth muscle (Davis et al, 2008). Because TGF-1 is a central pathological mediator of lung fibrosis (Cutroneo et al, 2007;Moore and Hogaboam, 2008), the induction of miR-21 by TGF-1 suggests that miR-21 may have a potential role in the pathogenesis of lung fibrosis. To validate the miRNA array data, Northern blotting was performed and showed that miR-21 was up-regulated in lungs from bleomycin-exposed mice as early as d 3 after bleomycin administration, reached its highest levels on d 14, and remained at the highest level until at least 24 d after bleomycin administration (Fig.…”

Effects of rapamycin against paraquat-induced pulmonary fibrosis in mice

“…Previous studies have demonstrated that TGF-β1 contributes to the progress of PQ-induced lung fibrosis (Chen C.M. et al, 2005;Cutroneo et al, 2007). Moreover, inhibition of TGF-β1 activity or its signaling pathways can significantly attenuate PQ-induced pulmonary fibrosis (Chen Y. et al, 2013).…”

Deficiency of α7 Nicotinic Acetylcholine Receptor Attenuates Bleomycin-Induced Lung Fibrosis in Mice

“…TGF-β signaling and transcription of fibrotic genes is essential for fibrogenesis (68,69). Both lung epithelial cells (21) and fibroblasts ( Figure 8A) express α7 nAChR.…”