Asbestos causes
asbestosis and
malignancies by mechanisms that are not fully established. Alveolar epithelial cell (AEC) injury and repair are crucial determinants of the fibrogenic potential of noxious agents such as
asbestos. We previously showed that mitochondrial
reactive oxygen species mediate
asbestos-induced AEC intrinsic apoptosis and that mitochondrial human 8-oxoguanine-DNA glycosylase 1 (OGG1),
a DNA repair
enzyme, prevents
oxidant-induced AEC apoptosis. We reasoned that OGG1 deficiency augments
asbestos-induced
pulmonary fibrosis. Compared with intratracheal instillation of PBS (50 μl) or
titanium dioxide (100 μg/50 μl),
crocidolite or Libby
amphibole asbestos (100 μg/50 μl) each augmented
pulmonary fibrosis in wild-type C57BL/6J (WT) mice after 3 weeks as assessed by histology,
fibrosis score, lung
collagen via Sircol, and
type 1 collagen expression; these effects persisted at 2 months. Compared with WT mice, Ogg1 homozygous knockout (Ogg1(-/-)) mice exhibit increased
pulmonary fibrosis after
crocidolite exposure and apoptosis in cells at the bronchoalveolar duct junctions as assessed via cleaved
caspase-3 immunostaining. AEC involvement was verified by colocalization studies using
surfactant protein C.
Asbestos increased endoplasmic reticulum stress in the lungs of WT and Ogg1(-/-) mice. Compared with WT, alveolar type 2 cells isolated from Ogg1(-/-) mice have increased
mtDNA damage, reduced mitochondrial
aconitase expression, and increased P53 and cleaved
caspase-9 expression, and these changes were enhanced 3 weeks after
crocidolite exposure. These findings suggest an important role for AEC
mtDNA integrity maintained by OGG1 in the pathogenesis of
pulmonary fibrosis that may represent a novel therapeutic target.