Revisiting Cell Death Responses in Fibrotic Lung Disease: Crosstalk between Structured and Non-Structured Cells

Abstract

Fibrosis is a life-threatening disorder caused by excessive formation of connective tissue that can affect several critical organs. Innate immune cells are involved in the development of various disorders, including lung fibrosis. To date, several hematopoietic cell types have been implicated in fibrosis, including pro-fibrotic monocytes like fibrocytes and segregated-nucleus-containing atypical monocytes (SatMs), but the precise cellular and molecular mechanisms underlying its development remain unclear. Repetitive injury and subsequent cell death response are triggering events for lung fibrosis development. Crosstalk between lung structured and non-structured cells is known to regulate the key molecular event. We recently reported that RNA-binding motif protein 7 (RBM7) expression is highly upregulated in the fibrotic lung and plays fundamental roles in fibrosis development. RBM7 regulates nuclear degradation of NEAT1 non-coding RNA, resulting in sustained apoptosis in the lung epithelium and fibrosis. Apoptotic epithelial cells produce CXCL12, which leads to the recruitment of pro-fibrotic monocytes. Apoptosis is also the main source of autoantigens. Recent studies have revealed important functions for natural autoantibodies that react with specific sets of self-antigens and are unique to individual diseases. Here, we review recent insights into lung fibrosis development in association with crosstalk between structured cells like lung epithelial cells and non-structured cells like migrating immune cells, and discuss their relevance to acquired immunity through natural autoantibody production.

Evaluation of possible role of fluoride in pathogenesis of oral submucous fibrosis: A pilot study

“…Furthermore, direct mucosal exposure to fluoride causes tissue damage, including to the oral mucosa 24 that may relate to OSMF's postulated defective wound healing pathogenesis 25,26 following chronic injury. Specifically, repetitive injury triggers extensive apoptosis in the epithelium 27 . This induces proliferation of activated myofibroblasts and fibrotic lesion formation, representing critical epithelium‐myofibroblast interactions driving fibrosis 27 …”

“…Specifically, repetitive injury triggers extensive apoptosis in the epithelium. 27 This induces proliferation of activated myofibroblasts and fibrotic lesion formation, representing critical epithelium-myofibroblast interactions driving fibrosis. 27 Therefore, based on the above observations and preliminary results of the present study, we hypothesize that fluoride elicits profibrotic effects through several mechanisms (Figure 4).…”

“…27 This induces proliferation of activated myofibroblasts and fibrotic lesion formation, representing critical epithelium-myofibroblast interactions driving fibrosis. 27 Therefore, based on the above observations and preliminary results of the present study, we hypothesize that fluoride elicits profibrotic effects through several mechanisms (Figure 4). These include its electronegativity, direct tissue damaging abilities, enzyme inhibition, oxidative stress induction, and interference with mitochondrial and collagen function.…”

CXC Chemokines in the Pathogenesis of Pulmonary Disease and Pharmacological Relevance

“…Pulmonary fibrosis (PF) is a chronic and progressive lung disease characterized by abnormal inflammatory wound healing and excessive deposition of extracellular matrix (ECM) [ 87 ]. Studies indicate that CXC chemokines and CXCRs play a role in PF.…”

“…CXCL12 acts through CXCR4, a receptor with a role in many biological processes including bone marrow- (BM-) derived stem cell activation and mobilization [ 90 ]. Fukushima et al [ 87 ] identified RNA-binding protein 7 (RBM7) and CXCL12 as important components of fibrosis development as both are enhanced in the fibrotic phase. RBM7 orchestrates a cascade of apoptotic events in the lung epithelium as a result of nuclear degradation of NEAT1 noncoding RNA (ncRNA).…”