SOURCE: Xtalks

Xtalks Webinars

October 28, 2015 07:30 ET

Disease Relevant In Vitro and In Vivo Models for Lung Fibrosis, New Webinar Hosted by Xtalks

TORONTO, ON--(Marketwired - October 28, 2015) - The live broadcast takes place on Thursday, November 12, 2015 at 11am EST (4pm GMT). The presenters include experts from Charles River: Dr. Alan Young, Business Development Manager for Respiratory Pharmacology, Dr. Jeroen DeGroot, Director of Cell Biology, and Dr. Vince Russell, Senior Director of Pharmacology, Discovery Services.

Fibrosis is characterized by excessive deposition of extracellular matrix due to exaggerated repair in response to damage. While the initiating event(s) and underlying pathophysiological processes vary between organs and diseases, common features include the involvement of inflammation, appearance of myofibroblasts, and changes in tissue architecture and function. In lung fibrosis, persistent and non-resolving injury to the alveolar epithelium is thought to drive the disease. The complex interactions between various cell types involved demand state-of-the art in vitro and in vivo models to enable the discovery and development of new drugs for fibrotic diseases.

Charles River has characterized numerous cell-based and animal models of lung fibrosis. In this webinar, we describe the pharmacological characterization of these models, including biomarker profile, histopathological and imaging-based readouts. The extensive data compiled for these models provide a comprehensive platform to first assess lung fibrosis targets and, later, efficacy of prospective anti-fibrotic therapies.

Primary human bronchial epithelial cells and fibroblasts isolated from donors diagnosed with idiopathic pulmonary fibrosis (IPF) and control donors were cultured in 96-well format. Trans-differentiation was induced with TGF-β and assessed by high content imaging (INCell 2200) following immunostaining for fibronectin (EMT in the epithelial cells) and αSMA (FMT in the fibroblasts). The effects of SB525334 (ALK5 inhibitor; assay positive control), pirfenidone, nintedanib, imatinib, MB06322, thalidomide, N-acetyl cysteine, tofacitinib and GSK2126458 were evaluated.

Lung fibrosis was induced in vivo using bleomycin administered to the lungs of both rats and mice and the effects followed for up to 56 days. Key endpoints included changes in body weight, clinical signs, respiratory and lung function parameters, assessment of inflammatory mediators in the BALF, determination of biomarkers in the sera, measurement of collagen deposition (as determined by hydroxyproline determination and imaging of lung tissue), histopathology observed in the lung (graded by Modified Ashcroft score and imaging modalities) and molecular MALDI imaging. The effects of clinically relevant compounds such as nintedanib and pirfenidone have also been investigated.

Both EMT and FMT assays were compatible with high throughput screening of small molecules and RNAi vectors. Signal/background ratio, vehicle tolerance, assay window and intra and inter-assay variability all passed pre-set QC criteria. Nintedanib and GSK2126458 inhibited EMT and FMT. Imatinib and MB06322 inhibited FMT but not EMT. The other compounds did not modulate trans-differentiation (up to 10µM).

Following dosing with bleomycin, multiple lung function parameters were changed, with peak changes occurring at D14 post-administration. Concomitant with this was a clear increase in lung inflammation as measured by inflammatory cell infiltrate into the lung. A neutrophilic infiltration was observed which peaked at D14 and recovered by D28. Macrophage numbers continued to increase out to D28. A similar pattern in the BALF was seen for inflammatory mediators such as TNF and KC/GRO. Inflammatory and fibrotic changes at necropsy were consistent with progressive fibrosis, with clear fibrotic lesions apparent from D21 onwards, as well as increases in lung hydroxyproline and collagen deposition. A combination of MALDI imaging and microscopy allowed monitoring the distribution of bleomycin in the lung, as well as the dynamics of (novel) fibrosis markers.

Primary human cell-based assays allow evaluation of compounds targeting various molecular mechanisms. In vivo, the combination of multiple endpoints allows detailed assessment of the potential anti-fibrotic efficacy of both small and large molecules when dosed both therapeutically and prophylactically.

To learn more about this event visit: Disease Relevant In Vitro and In Vivo Models for Lung Fibrosis

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