الفهرس 
Introduction and aim of the workOnly 14 pages are availabe for public view
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Abstract
ILDs refer to an umbrella term including numerous chronic lung conditions with varying degrees of fibrosis. While some ILDs, such as RA and SLE-related ILDs, have a high correlation to connective tissue diseases, IPF has an obscure cause despite a history of exposure to medical, occupational, and environmental factors.
Genetic studies of ILDs have contributed to an improved understanding of disease vulnerability and the identification of potential targets for future investigations. GWAS has found several variants in the genome related to the occurrence of complicated respiratory characteristics. Additionally, GWAS and subsequent fine-mapping revealed a novel SNP, rs12979860, in interferon lambda-3 to be related to liver inflammation and fibrosis in different disease etiologies. IFN-λ3 was also proven to be a powerful pro-inflammatory cytokine produced mostly by epithelial and immune cells, with a prominent role at epithelial surfaces. The pro-inflammatory action of IFN-λ3 may be due to the fact that it increases the mobilization of immune cells to the inflammation site. Our research is the first to precisely describe the role or mechanism of IFN-λ3 in fibrotic ILD.
The innate immune system, which is armed with PRRs, the majority of which are TLRs, is the first line of defense against infections. TLRs are widely used to detect pathogens and endogenous DAMPs, with TLR4 being the most extensively researched. TLR4, which was found to be triggered by PAMPs and DAMPs to sustain sterile tissue injury, is regarded as a key mediator in the development of pulmonary fibrosis. TLR4 is a primary regulator in the activation of the pro-inflammatory transcription factor NF-κB and accelerates IL-1β and TNF-α expressions. Furthermore, TLR4 stimulation by LPS has been reported to stimulate the production of IFN-λ3 by MDDC in vitro.
We therefore postulate that TLR4 and pro-inflammatory cytokines are the fundamental processes by which IFN-λ3 affects the lung. This study aims to investigate for the first time the association between a specific genetic polymorphism (rs12979860 C/T in the IFN-λ3) and the pathogenesis of fibrotic ILD. In addition to examining the fundamental role and molecular mechanism of the IFNL3 gene in pulmonary fibrosis via the TLR4/pro-inflammatory cytokine pathway.
Furthermore, the basic function and molecular mechanism of the IFNL3 gene in pulmonary fibrosis via the TLR4/pro-inflammatory cytokine pathway is being investigated as well as the association of the IFNL3 rs12979860 genotype with ILDs. Besides, mRNA expression of IFNL3, TLR4, NF-κB, IL-1β, and TNF-α was demonstrated in PBMCs. Simultaneously, a BLM -induced lung fibrosis mice model was established.
The primary conclusion of this research was the association of IFNL3 rs12979860 genotypes with ILD pathogenesis. Furthermore, the IFNL3 rs12979860 CC genotype could maintain tissue inflammation via its effect on the expression of TLR4, IL-1β, and TNF-α but not NF-kB. Thus, the pro-inflammatory and pro-fibrotic role played by IFN-λ3 may be mediated via its effect on the TLR4/pro-inflammatory mediators pathway. PAMPs and DAMPs on lung tissue trigger TLR4, which has been shown to raise IFN-λ3, which consequently increases the infiltration of immune cells to the site of inflammation. This data established IFN-λ3 as a novel target for new drug development and opened the way for additional research that can enhance the quality of life for ILD patients.