Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible lung disease of unknown etiology with limited survival. IPF incidence and prevalence increase significantly with aging, which is associated with an age-related accumulation of oxidative DNA damage. The Mutyh gene is involved in the base excision repair (BER) system, which is critical for repairing the misincorporated adenine that is opposite to the oxidized guanine base, 8-oxoguanine, and maintaining the fidelity of DNA replication. We used Mutyh knockout mice and a bleomycin-induced pulmonary fibrosis model to test the effect of MUTYH deficiency on lesion progression. Unexpectedly, a much less severe lesion of pulmonary fibrosis was observed in Mutyh−/− than in Mutyh+/+mice, which was supported by assay on protein levels of TGF-β1 and both fibrotic markers, α-SMA and Vimentin, in pulmonary tissues of the model animals. Mechanically, MUTYH deficiency prevented the genomic DNA of pulmonary tissue cells from the buildup of single-strand breaks (SSBs) of DNA and maintained the integrity of mtDNA. Furthermore, increased mitochondrial dynamic regulation and mitophagy were detected in pulmonary tissues of the bleomycin-induced Mutyh−/− model mice, which could reduce the pulmonary epithelial cell apoptosis. Our results suggested that MUTYH deficiency could even induce protective responses of pulmonary tissue under severe oxidative stress.
Highlights
Idiopathic pulmonary fibrosis (IPF) is the most common form of idiopathic interstitial pulmonary disease, and it is characterized by extracellular matrix deposition, which leads to a progressive decline in lung function
To test whether MutY homolog (MUTYH)-deficient mice were more prone to pulmonary fibrosis, Mutyh knockout (Mutyh-/-) and wild-type (Mutyh+/+) mice were subjected to intratracheal administration of BLM to induce pulmonary fibrosis
These mice were divided into different groups and euthanized on day 7 (D7), 14 (D14), or 28 (D28) after the intratracheal administration of a single dose of BLM, which corresponded to the inflammation phase, transitional phase of inflammation/fibrosis, and late stage with increased deposition of lung collagen, respectively (Figure 1(a))
Summary
Idiopathic pulmonary fibrosis (IPF) is the most common form of idiopathic interstitial pulmonary disease, and it is characterized by extracellular matrix deposition, which leads to a progressive decline in lung function. The development of IPF remains to be understood, increased oxidative stress and mitochondrial dysfunction have been considered to contribute to its pathogenesis [2]. Accumulating evidence shows that oxidative stress induces mitochondrial DNA (mtDNA) damage and plays a key role in pulmonary fibrosis and other age-related diseases. 8-oxoguanine (8-oxoG) is a major ROS-induced oxidized base lesion in DNA, and its accumulation is associated with mitochondrial dysfunction and multiple organ injury [3, 4]. This lesion is mutagenic, and it is a major cause of G:C to T:A transversions in genomic DNA [5, 6].
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