TLR4/NF-KB SIGNALING PATHWAY IS A KEY PATHOGENIC EVENT OF LUNG INJURY IN BLEOMYCIN-INDUCED PULMONARY FIBROSIS IN A MOUSE MODEL

Mostafa Sabry

doi:10.21608/ajps.2020.86019

Abstract

Interstitial lung disease (ILD) comprises many chronic lung diseases with various degrees of inflammation and fibrosis. Idiopathic pulmonary fibrosis (IPF) is a specific lung disorder characterized by progressive fibrosis leading to end-stage lung disease, respiratory failure, and fatal outcome. The toll like receptor (TLR) family serves as an important regulatory role in the innate immune system. Recently, several studies implicated TLR signaling in the proinflammatory response of a variety of endogenous and exogenous stimuli within the lung. Innate immune activation via TLR4 contributes to lung injuries but its role in tissue remodeling during ILD is still unclear. The current study aimed to investigate role of lungTLR4, nuclear factor kappa B (NF-kB), transforming growth factor-β (TGF-β) and interleukin 1B (IL1B) in the pathogenesis of IPF. We examined the expression pattern of TLR4, NF-kB, TGF and IL1B after one and three weeks of bleomycin-induced pulmonary fibrosis in a mouse model. Expression of TLR4 and its downstream modulator NF-kB were markedly elevated. Consequently, expression of profibrogenic cytokine TGF-β and inflammatory cytokines IL1B were induced in all grades of pulmonary fibrosis of mice model. Furthermore, there was an increase in interstitial collagen deposition side by side with induction of the activity of some pathophysiological enzymes and uric acid. In conclusion, our findings exhibit the importance of TLR4/NF-kB as significant mediators in fibrotic lung injury and open the door for future studies that can improve the lifestyle of IPF patients.

Highlights

Interstitial lung diseases (ILDs), a heterogeneous group of disorders characterized by inflammatory and fibrotic lung diseases with high morbidity and mortality, defined as diffuse parenchymal lung disease(Ge et al, 2020)
The most extensively studied type of ILD is idiopathic pulmonary fibrosis (IPF), which occurs mainly in adults aged over 60 years and is characterized by progressive pulmonary fibrosis, decline in lung function and high mortality(Kolb et al, 2019)
There has been a conception in IPF pathogenesis that fibrogenesis inflammatory driven process results from recurrent microinjury of alveolar epithelial cells followed by repair processes. (Balestro et al, 2016)

Summary

Introduction

Interstitial lung diseases (ILDs), a heterogeneous group of disorders characterized by inflammatory and fibrotic lung diseases with high morbidity and mortality, defined as diffuse parenchymal lung disease(Ge et al, 2020). The most extensively studied type of ILD is idiopathic pulmonary fibrosis (IPF), which occurs mainly in adults aged over 60 years and is characterized by progressive pulmonary fibrosis, decline in lung function and high mortality(Kolb et al, 2019). The model of bleomycin (BLM)-induced lung fibrosis represents the most commonly applied experimental model. Tissue damage and inflammation are important triggers for regeneration and fibrosis. Tissue damage induces inflammation in general, it determines the type and polarization of inflammation by recruiting and activating a variety of different cells types of the innate and adaptive immune system(Mack, 2018)

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