Thesis 2018: TIMP3 (SFD) , MMP-28 (epilysiini) . Raamissa COPD ja IPF

J Proteomics. 2018 Oct 30;189:23-33. doi: 10.1016/j.jprot.2018.02.027. Epub 2018 Mar 1.

Quantitative proteomic characterization of the lung extracellular matrix in chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis.

Åhrman E¹, Hallgren O², Malmström L³, Hedström U⁴, Malmström A⁵, Bjermer L², Zhou XH⁶, Westergren-Thorsson G⁷, Malmström J⁸.

Abstract

Remodeling of the extracellular matrix (ECM) is a common feature in lung diseases such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Here, we applied a sequential tissue extraction strategy to describe disease-specific remodeling of human lung tissue in disease, using end-stages of COPD and IPF. Our strategy was based on quantitative comparison of the disease proteomes, with specific focus on the matrisome, using data-independent acquisition and targeted data analysis (SWATH-MS). Our work provides an in-depth proteomic characterization of human lung tissue during impaired tissue remodeling. In addition, we show important quantitative and qualitative effects of the solubility of matrisome proteins. COPD was characterized by a disease-specific increase in ECM regulators, metalloproteinase inhibitor 3 (TIMP3) and matrix metalloproteinase 28 (MMP-28), whereas for IPF, impairment in cell adhesion proteins, such as collagen VI and laminins, was most prominent. For both diseases, we identified increased levels of proteins involved in the regulation of endopeptidase activity, with several proteins belonging to the serpin family. The established human lung quantitative proteome inventory and the construction of a tissue-specific protein assay library provides a resource for future quantitative proteomic analyses of human lung tissues. SIGNIFICANCE: We present a sequential tissue extraction strategy to determine changes in extractability of matrisome proteins in end-stage COPD and IPF compared to healthy control tissue. Extensive quantitative analysis of the proteome changes of the disease states revealed altered solubility of matrisome proteins involved in ECM regulators and cell-ECM communication. The results highlight disease-specific remodeling mechanisms associated with COPD and IPF.

KEYWORDS:

COPD; IPF; Lung tissue; Matrisome; Quantitative proteomics; SWATH-MS

PMID:

29501846

DOI:

10.1016/j.jprot.2018.02.027

TACE, SIRT-1 ,TIMP-3, IBD, resveratroli

https://www.ncbi.nlm.nih.gov/pubmed/24548422

Cytokine. 2014 Mar;66(1):30-9. doi: 10.1016/j.cyto.2013.12.010. Epub 2014 Jan 4.

Involvement of TACE in colon inflammation: a novel mechanism of regulation via SIRT-1 activation.

Sharma M¹, Mohapatra J¹, Wagh A¹, Patel HM¹, Pandey D¹, Kadam S¹, Argade A², Deshpande SS³, Shah GB³, Chatterjee A⁴, Jain MR¹.

Abstract

TNF-α converting enzyme (TACE) processes the membrane TNF-α to release the bioactive soluble TNF-α. Several evidences suggest the involvement of TNF-α and TACE in inflammatory bowel disease (IBD). Tissue inhibitor of metalloproteinase (TIMP)-3, an endogenous inhibitor of TACE, is positively associated with silent information regulator (SIRT)-1. We aimed to study the expression of TACE, TIMP-3 and SIRT-1 at different stages of colitis and how TACE is regulated in response to SIRT-1 activation.

 Acute colitis was induced by 3.5% dextran sulfate sodium (DSS) in drinking water for 5days and levels of cytokines and mRNA expression of TACE, TIMP-3 and SIRT-1 were measured in colon at different time intervals. Next, the effect of SIRT-1 activator (resveratrol) or a selective TACE inhibitor (compound 11p) treatment was evaluated. Elevated levels of TNF-α, interleukin (IL)-6, IL-1β, interferon (IFN)-γ and IL-17 were observed during DSS exposure phase which restored to the normal level after DSS removal. A significant increase in TACE and suppression in TIMP-3 and SIRT-1 mRNA level was observed during DSS exposure phase which reverts back to normal towards the remission phase. Treatment with resveratrol significantly elevated SIRT-1 and TIMP-3 and suppressed TACE mRNA expression and was associated with amelioration of disease. Furthermore, treatment with selective TACE inhibitor significantly suppressed body weight loss, disease activity index, colonic myeloperoxidase activity and the elevated levels of cytokines after DSS challenge. These results strongly emphasize the involvement of TACE in colon inflammation and inhibition of TACE directly or indirectly via SIRT-1 activation ameliorates colitis.

KEYWORDS:

Inflammatory bowel disease; SIRT-1; TNF-α; TNF-α converting enzyme

PMID:

24548422

DOI:

10.1016/j.cyto.2013.12.010