Lack of ZNF365 Drives Senescence and Exacerbates Experimental Lung Fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is characterized by aberrant activation of the alveolar epithelium, the expansion of the fibroblast population, and the accumulation of extracellular matrix. Global gene expression of human lung fibroblasts stimulated with TGFβ-1, a strong fibrotic mediator revealed the overexpression of ZNF365, a zinc finger protein implicated in cell cycle control and telomere stabilization. We evaluated the expression and localization of ZNF365 in IPF lungs and in the fibrotic response induced by bleomycin in WT and deficient mice of the orthologous gene Zfp365. In IPF, ZNF365 was overexpressed and localized in fibroblasts/myofibroblasts and alveolar epithelium. Bleomycin-induced lung fibrosis showed an upregulation of Zfp365 localized in lung epithelium and stromal cell populations. Zfp365 KO mice developed a significantly higher fibrotic response compared with WT mice by morphology and hydroxyproline content. Silencing ZNF365 in human lung fibroblasts and alveolar epithelial cells induced a significant reduction of growth rate and increased senescence markers, including Senescence Associated β Galactosidase activity, p53, p21, and the histone variant γH2AX. Our findings demonstrate that ZNF365 is upregulated in IPF and experimental lung fibrosis and suggest a protective role since its absence increases experimental lung fibrosis mechanistically associated with the induction of cell senescence.

Reduced Proliferative Capacity and Defense against <i>Staphylococcus aureus</i> in Human Nasal Mucosal Epithelium Lacking ZNF365

“…In a study on pulmonary fibrosis, it was found that mice ZNF365 knocked down resulted in enhanced fibrosis in response to bleomycin stimulation. The expression of collagen 1 (Col1a1) and collagen 3 (Col1a3), two genes associated with EMT, was also found to be upregulated in fibroblasts with ZNF365 knocked down [13]. This is consistent with our research results.…”

“…S. aureus has been detected in more than half of the nasal cavity in CRSwNP patients with S. aureus fixation [7,8]. Moreover, specific IgE against S. aureus enterotoxin is found in approximately 50% of NP tissue homogenates [13]. Due to the dysregulation of nasal flora in CRSwNP patients, the opportunistic pathogen S. aureus is presently predominant in its fixation value.…”

“…In cells with extremely shortened telomeres, p53 activation of ZNF365 promotes genome stability [12]. In human lung fibroblasts and A549 epithelial cell lines, ZNF365 gene deletion significantly reduces cell growth rate, exerting a significant effect on cell cycle regulation [13]. This causes G1/S phase arrest and delayed mitotic progression [4].…”

Procyanidin C1 inhibits bleomycin‐induced pulmonary fibrosis in mice by selective clearance of senescent myofibroblasts

“…[6][7][8] Notably, in the US, the incidence in individuals aged 65 years and older soars to a staggering 93.7 cases per 100 000 persons per year, accompanied by a prevalence of 494.5 cases per 100 000 persons per year. 9 Additionally, in bleomycin (BLM)-treated aging mice, a more severe and persistent pulmonary fibrosis has been observed compared with that in their younger counterparts 10,11 These findings imply that aging is a crucial risk factor for pulmonary fibrosis. 12 Cellular senescence, a hallmark of aging, is driven by several factors, including telomere attrition, oxidative stress, DNA damage, and stress-induced cell cycle arrest.…”