The Pulmonary Disease Research Lab
Part of the Pulmonary Division at Meir Medical Center
Affiliated to Sackler Faculty of Medicine at Tel-Aviv University
Research
We are interested the effects of the micro-environment on pulmonary disease progression, with the focus on fibroblasts and fibrotic processes. In addition to the basic research, our lab supports the clinical trials at the department in fields such as pulmonary hypertension, ARDS and COPD.
Primary Cell Cultures and Bio-
bank
In all biological systems, we use primary, newly extracted human lung tissue derived fibroblasts.
In addition, we created a bio-bank that includes various Interstitial Lung Disease (ILD) and rheumatic disease samples.
The Team
Prof. David Shitrit, MD
Gali Epstein Shochet, PhD
Head of the Pulmonary Division
at Meir Medical Center
Principle Investigator
Past and current students
Elisabetha Brook
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Becky Bardenstein-Wald
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Vered Danino
Liran Dembitz
Noa Moshkovitz
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Conditioned extracellular matrix (ECM) in-vitro system
The ECM - fibroblast interaction is difficult to explore.
Therefore, we established a human primary cell based IPF-conditioned matrix (CM) system. This system enables the in-vitro study of this complex interaction, as well as the efficacy of new compounds in preventing fibrotic processes.
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Respirology. 2018 Aug;23(8):756-763. doi: 10.1111/resp.13287
Alon Pomerantz​
Fibroblast-matrix interplay: Nintedanib and pirfenidone modulate the effect of IPF fibroblast-conditioned matrix on normal fibroblast phenotype
IPF fibroblasts alter the ECM, thus creating a CM that further propagates an IPF-like phenotype in normal fibroblasts. This assay demonstrated differences in drug activities for approved IPF drugs at clinically relevant concentrations. Thus, the matrix-fibroblast phenotype interplay might be a relevant assay to explore drug candidates for IPF treatment.
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Respirology. 2018 Aug;23(8):756-763. doi: 10.1111/resp.13287
Galectin-3 levels are elevated following nintedanib treatment
Currently, the Gal-3 inhibitor TD139 is being tested in phase II clinical trials. Since this treatment is given ‘on top’ of nintedanib, it is important to estimate its effect on Gal-3 levels. Therefore, we evaluated the impact of nintedanib on Gal-3 expression using both in vitro and in vivo models, in addition to serum samples from patients with IPF.
We found that nintedanib elevates Gal-3 levels in both experimental models, along with patient samples. These findings highlight the possibility of using combined inhibition therapy for patients with IPF.
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Therapeutic Advances in Chronic DiseaseVolume 11, January-December 2020
Inhalation: A means to explore and optimize nintedanib's pharmacokinetic/pharmacodynamic relationship
Oral nintedanib is marketed for the treatment of idiopathic pulmonary fibrosis (IPF). While effective slowing fibrosis progression, as an oral medicine nintedanib is limited. To reduce side effects and maximize efficacy, nintedanib was reformulated as a solution for nebulization and inhaled administration. In this work, we used our IPF-CM system and an in-vivo model to show that pharmacokinetic elements important for nintedanib activity can be delivered using infrequent, small inhaled doses to achieve oral equivalent-to-superior pulmonary activity.
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Pulm Pharmacol Ther​. 2020 Aug;63:101933.
Integrin alpha-5 silencing leads to myofibroblastic differentiation in IPF derived human lung fibroblasts
The term ‘fibroblast’ covers a heterogeneous cell population in idiopathic pulmonary fibrosis (IPF). Previously, we showed that ITGA5 is elevated in IPF-HLFs and that IPF secreted factors can elevate its level in normal-HLFs. In this following work we show that ITGA5 expression facilitates a more aggressive proliferative phenotype in IPF-HLFs. Downregulation of this integrin results in myofibroblastic differentiation, which is accompanied by elevated ITGA8.
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https://doi.org/10.1177/2040622320936023
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Published Work
