Pulmonary fibrosis is characterized by the progressive accumulation of fibroblasts within the alveolar wall and airspace with subsequent deposition of collagen in the distal airspace. This is manifested clinically by severe shunt physiology and often leads to respiratory failure and death. Unfortunately, therapeutic modalities for fibroproliferative lung diseases, which suppress inflammation, have had limited clinical benefit in terms of halting progressive fibrosis. This suggests therapy targeting fibroblasts is essential. It is well documented that some patients with extensive alveolar fibrosis are capable of full recovery. Experimental evidence indicates that removal of unwanted fibroblasts occurs by apoptosis at a critical timepoint during tissue repair allowing restoration of normal anatomic patterns. Therefore, we hypothesize that selective removal of fibroblasts actively participating in the fibrotic process at a critical time period after lung injury will be beneficial in attenuating pulmonary fibrosis and promoting lung repair. In a proof of principle study we plan to utilize transgenic mice we have developed expressing HSV-TK from the mouse alpha 2 type I [alpha2(I)] collagen promoter to test our hypothesis. To selectively target fibroblasts, an alpha2(I) collagen promoter that has selective expression by fibroblasts will be used. To achieve fibroblast ablation, we will employ the thymidine kinase gene of the herpes simplex virus (HSV-TK). Those fibroblasts actively participating in the fibrotic process (e.g., those actively synthesizing large amounts of type I collagen) will express transgene derived HSV-TK and metabolize the antiviral agent ganciclovir (GCV) to toxic nucleotide analogs which disturb nucleic acid synthesis and induce cell death. To create pulmonary fibrosis, the murine model of bleomycin-induced pulmonary fibrosis will be utilized. In this model of pulmonary fibrosis alpha2(I) collagen gene expression by fibroblasts is markedly increased. Therefore fibroblast ablation will be regulated both regionally by the use of the alpha2(I) collagen promoter to target lung fibroblasts actively synthesizing type I collagen and temporally by when GCV is administered.
| Xia, Hong; Diebold, Deanna; Nho, Richard et al. (2008) Pathological integrin signaling enhances proliferation of primary lung fibroblasts from patients with idiopathic pulmonary fibrosis. J Exp Med 205:1659-72 |
| Tian, Bin; Han, Lei; Kleidon, Jill et al. (2003) An HSV-TK transgenic mouse model to evaluate elimination of fibroblasts for fibrosis therapy. Am J Pathol 163:789-801 |
