Dataset Information

Targeting Mechanics-Induced Fibroblast Activation through CD44-RhoA-YAP Pathway Ameliorates Crystalline Silica-Induced Silicosis.

ABSTRACT: Silicosis is pneumoconiosis of the lung, usually resulting from prolonged exposure to crystalline silica (CS). The hallmark of silicosis is excessive extracellular matrix (ECM) deposition produced by activated fibroblasts. Recent work demonstrated that excessive ECM-forming mechanical cues play an essential role in promoting fibroblast activation and perpetuating fibrotic pathologies. However, the detailed molecular mechanism still needs to be uncovered. Methods: NIH-3T3 fibroblasts were cultured on either 1 kappa (soft) or 60 kappa (stiff) gel-coated coverslips. A series of knockdown and reverse experiments in vitro were performed to establish the signaling for mechanics-induced fibroblast activation. An experimental model of silicosis was established by one-time intratracheal instillation of CS suspension. The cluster of differentiation 44 (CD44) antibody (IM7), dihydrotanshinone I (DHI) and verteporfin (VP) were used to explore the effect of CD44-RhoA-YAP signaling blockade on mechanics-induced fibroblast activation and CS-induced pulmonary fibrosis. Results: Matrix stiffness could induce nuclear translocation of the Yes-associated protein (YAP) through CD44 in fibroblasts. This effect required RhoA activity and F-actin cytoskeleton polymerization but was independent of Hippo pathway kinases, Mst 1 and Lats 1, forming CD44-RhoA-YAP signaling pathway. Pharmacological upstream blocking by CD44 antibody or downstream blockade of YAP by DHI or VP could attenuate fibroblast migration, invasion, proliferation, and collagen deposition. Furthermore, CD44-RhoA-YAP signaling blockade could alleviate CS-induced fibrosis and improve pulmonary function in vivo. Conclusion: CD44-RhoA-YAP signaling mediates mechanics-induced fibroblast activation. Targeting this pathway could ameliorate crystalline silica-induced silicosis and provide a potential therapeutic strategy to mitigate fibrosis.

SUBMITTER: Li S

PROVIDER: S-EPMC6691376 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Targeting Mechanics-Induced Fibroblast Activation through CD44-RhoA-YAP Pathway Ameliorates Crystalline Silica-Induced Silicosis.

Li Siyi S Li Chao C Zhang Yiting Y He Xiu X Chen Xi X Zeng Xinning X Liu Fangwei F Chen Ying Y Chen Jie J

Theranostics 20190709 17

Silicosis is pneumoconiosis of the lung, usually resulting from prolonged exposure to crystalline silica (CS). The hallmark of silicosis is excessive extracellular matrix (ECM) deposition produced by activated fibroblasts. Recent work demonstrated that excessive ECM-forming mechanical cues play an essential role in promoting fibroblast activation and perpetuating fibrotic pathologies. However, the detailed molecular mechanism still needs to be uncovered. <b>Methods</b>: NIH-3T3 fibroblasts were ...[more]

PMID: 31410197

Similar Datasets

Project description:The effect, if any, of age on the pulmonary toxicity induced by Min-U-Sil 5 crystalline silica exposure was investigated in rats. As part of the study, the changes in global gene expression profiles in the blood and lungs of the animals were determined. To conduct these studies, to determine if age influences the pulmonary response to crystalline silica exposure, two different age groups of healthy, male F344 rats were used. In this study the young age group of rats (6 months old at the time of exposure) was exposed to either air or crystalline silica (Min-U-Sil 5) (15 mg/m3, 6 hours/day, 5 days) by whole body inhalation. The young age group of rats simulates a group of workers who would be 18 to 20 years old. At two crystalline silica post-exposure time periods (1-day and 6-months) animals were euthanized and pulmonary inflammatory, cytotoxic, and oxidant responses were determined. Analysis of bronchoalveolar lavage parameters of toxicity such as oxidant generation and inflammation revealed significant changes in pulmonary toxicity in the crystalline silica exposed rats compared with the time-matched, air exposed control rats. The blood gene expression profiles showed only minimal changes, at both the time points, in the crystalline silica exposed rats compared with the controls. Specifically, there were a total of 5 genes significantly differentially expressed (fold change >1.5 and FDR p<0.05) in the one-day post-exposure group and no significantly differentially genes in the 6-month post-exposure group. However, the lung gene expression profiles showed substantial changes in the crystalline silica exposed animals at both one-day and 6-month post-exposure. Specifically, there were a total of 385 genes significantly differentially expressed (fold change >1.5 and FDR p<0.05) at the one-day post-exposure group and 317 genes significantly differentially expressed at the 6-month post-exposure. The data obtained from the present study demonstrated that crystalline silica inhalation exposure, under the conditions employed in the present study, resulted in significant changes in lung toxicity parameters and lung gene expression profile in the rats at both 1-day and 6-month post-exposure.

Project description:Silicosis and other respirable crystalline silica-associated diseases, most notably tuberculosis, have long been substantial causes of morbidity and mortality in South Africa. For the mining and non-mining industries, silicosis elimination programmes have been developed with milestones regarding reduction of levels of exposure to respirable crystalline silica (RCS) and targets regarding the date of eradication. The present paper explores the feasibility of achieving these targets by investigating the evidence that levels of exposure and silicosis incidence rates have declined by an appraisal of the methods for data collection and reporting. In the mining industry the silicosis elimination programme is supported by the development and advocacy of leading practices to reduce the exposure. RCS exposure data are routinely collected according to a Code of Practice (CoP) and the results are reported to the Mine Health and Safety Inspectorate. As the CoP and the actual workplace practices have been demonstrated to have some flaws, there is some concern about the accuracy of the actual exposure data and the data interpretation. The annually reported levels of exposure suggest a decline, however, the actual levels of RCS as well as the number of exposed workers, were not reported over the last few years. With regard to the silicosis incidence rates, a steady decline of new cases is reported. However, there is a risk of under-diagnosis and- reporting especially in former miners. In the non-mining industries, a systematic baseline of RCS exposure levels and silicosis incidence is lacking. The reporting by industries on assigning of the workforce to exposure categories seems to be fragmented and incomplete. Consequently, any evidence of progress toward achieving the silicosis elimination target cannot be documented. Both the silicosis elimination target and the exposure milestone are aspirational but are unlikely to be achieved. Nevertheless, the formal mining industry may get close. Exposure control interventions, especially in the non-mining industries, should be developed and implemented and pragmatic methods need to be put in place to identify sources of new silicosis cases for targeted intervention.

Project description:The effect, if any, of age on the pulmonary toxicity induced by Min-U-Sil 5 crystalline silica exposure was investigated in rats. As part of the study, the changes in global gene expression profiles in the blood and lungs of the animals were determined. To conduct these studies, to determine if age influences the pulmonary response to crystalline silica exposure, two different age groups of healthy, male F344 rats were used. In this study the old age group of rats (12 months old at the time of exposure) was exposed to either air or crystalline silica (Min-U-Sil 5) (15 mg/m3, 6 hours/day, 5 days) by whole body inhalation. The old age group of rats simulates a group of workers who would be 45 to 50 years old. At two crystalline silica post-exposure time periods (1-day and 6-months) animals were euthanized and pulmonary inflammatory, cytotoxic, and oxidant responses were determined. Analysis of bronchoalveolar lavage parameters of toxicity such as oxidant generation and inflammation revealed significant changes in pulmonary toxicity in the crystalline silica exposed rats compared with the time-matched, air exposed control rats. The blood gene expression profiles showed only minimal changes, at both the time points, in the crystalline silica exposed rats compared with the controls. Specifically, no genes were significantly differentially expressed (fold change >1.5 and FDR p<0.05) in the one-day post-exposure group and only 6 genes were significantly differentially expressed in the 6-month post-exposure group. However, the lung gene expression profiles showed substantial changes in the crystalline silica exposed animals at both one-day and 6-month post-exposure. Specifically, there were a total of 325 genes significantly differentially expressed (fold change >1.5 and FDR p<0.05) at the one-day post-exposure group and 3348 genes significantly differentially expressed at the 6-month post-exposure. The data obtained from the present study demonstrated that crystalline silica inhalation exposure, under the conditions employed in the present study, resulted in significant changes in lung toxicity parameters and lung gene expression profile in the rats at both 1-day and 6-month post-exposure.

Dataset Information

Targeting Mechanics-Induced Fibroblast Activation through CD44-RhoA-YAP Pathway Ameliorates Crystalline Silica-Induced Silicosis.

Publications

Targeting Mechanics-Induced Fibroblast Activation through CD44-RhoA-YAP Pathway Ameliorates Crystalline Silica-Induced Silicosis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets