A novel segmental challenge model for bleomycin-induced pulmonary fibrosis in sheep

Abstract

Fibrosis comparable to IPF was induced into isolated lung segments, without compromising the respiratory functioning of the animal. This model may have potential for investigating novel therapies for IPF by allowing direct comparison of multiple treatments with internal controls, and sampling and drug delivery that are clinically relevant.

Inhibition of the KCa3.1 Channel Alleviates Established Pulmonary Fibrosis in a Large Animal Model

“…The current evidence supporting the importance of the K Ca 3.1 channel and Ca 21 signaling in profibrotic and wound-healing responses in the lungs is based on in vitro studies (10,12,14), yet there is no reported work that has investigated whether these findings translate in vivo in a therapeutic setting. Therefore, we sought to determine the efficacy of inhibiting the K Ca 3.1 ion channel in a more clinically relevant setting using delayed administration of Senicapoc, a selective inhibitor of K Ca 3.1, after resolution of the early inflammatory response to bleomycin in our large animal (sheep) model for pulmonary fibrosis (20,21). In this study, we have demonstrated that oral administration of Senicapoc improved lung function, ameliorated BLMinduced fibrosis, and attenuated profibrotic responses in primary sheep lung fibroblasts.…”

“…Segmental lung compliance was calculated as previously described (20), using a custom-built segmental lung airway-monitoring system to monitor the segmental flow and pressure. A bronchoscope was wedged into an airway in the lung segment of interest and a constant flow (4.5 ml/s) of 5% CO 2 in air was passed through the working channel of the bronchoscope.…”

“…The differentially treated lung lobes from each sheep were processed for histological assessment using standard procedures from our laboratory (21). The degree of fibrotic injury in lung parenchyma of each lobe was assessed by an experienced pathologist blinded to the treatment groups using a semiquantitative scoring system, as previously described (20), using hematoxylin and eosin-stained sections. Masson's trichrome-stained slides were also quantified in a blinded fashion to give an indication of changes for overall extracellular matrix content within the parenchymal tissue using previously described methods, to give the fibrotic fraction of the tissue in each lobe (20).…”

“…Animal models for the study of pulmonary fibrosis provide a useful tool to test novel therapies in an in vivo setting, although they have come under many levels of criticism in regard to their translational capabilities of mimicking the clinical setting (19). We have developed a large animal model of pulmonary fibrosis in sheep, which uses a segmental bleomycin challenge regime to induce fibrosis in individual lobes of the animal (20,21). The use of sheep provides a lung with comparable structural and functional properties to human lungs, including elastance and compliance of the lung (22), as well as the distribution and organization of extracellular matrix components.…”

“…In the current study, we investigated the in vivo effects of blocking K Ca 3.1 ion channel signaling with the inhibitor, Senicapoc, during the early fibrogenic response in our sheep model (20). Specifically, we examined the impact that K Ca 3.1 blockade had on lung function, pathology, and collagen deposition (the basis of fibrosis) after bleomycin administration to induce fibrosis within specific lobes of the lungs.…”