Small airway remodeling in a sheep model of bleomycin-induced pulmonary fibrosis

Abstract

Background Although IPF is described traditionally as a disease affecting lung parenchyma, there is renewed interest in the alterations in the structure and function of the small airways in both IPF patients, and animal models of pulmonary fibrosis. Small airway remodeling may contribute to the pathophysiology of pulmonary fibrosis. Given the dearth of knowledge of small airway changes in pulmonary fibrosis, this study aims to assess the structural remodeling, as well as functional changes associated with bleomycin-injured small airways in a sheep model of pulmonary fibrosis. Materials and Methods Two separate lung segments in ten sheep received two challenges of either 3 IU bleomycin, or saline (control), two weeks apart. The animals were euthanized seven weeks after the final bleomycin injury. Airflow resistance in the infused segments was measured with a wedged-bronchoscope procedure. This parameter was measured at baseline before bleomycin/saline-infusion, and at 2-, 4-, and 7-weeks after the final bleomycin-infusion. Inflammation and fibrosis in the airways were assessed by semi-quantitative morphological parameters. The density of blood vessels in the small airway walls was assessed in lung tissue sections immuno-stained with antibodies against collagen type IV. Results There were a number of changes in the distal airways of bleomycin-infused lung segments. Bleomycin exposure significantly elevated airway resistance in these lung segments when compared to saline-infused control lung segments. In the peribronchial and peribronchiolar regions of the small airways, there were significantly increased levels of inflammation, fibrosis, airway wall area, and collagen deposition in bleomycin-infused airways when compared to saline-infused airways. Bronchial blood vessel density was not significantly different between bleomycin-and saline-infused lung segments. Conclusions In summary, our results indicate that the distal airways are involved in the pathology induced by bleomycin in this sheep model. This suggests that the sheep model may be useful for studying small airway remodeling in pulmonary fibrosis.