BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory lung disorder driven not only by tobacco smoke (TS) but also by environmental toxicants, including particulate matter (PM) and heavy metals such as lead (Pb) and cadmium (Cd). Although oxidative stress and inflammatory cell death are central to COPD pathogenesis, effective disease-modifying therapeutic targets remain limited. Here, we identify that nerve injury-induced protein 1 (Ninjurin1, Ninj1), a damage-responsive cell adhesion molecule implicated in inflammatory cell death, as a previously unrecognized mediator of toxicant-induced COPD-like pathology. METHODS: We designed and screened a panel of 22 2'-O-methoxyethyl (2'-MOE) gapmer antisense oligonucleotides (ASOs) targeting Ninj1. Cell type-specific knockdown efficiency was assessed by flow cytometry and real-time PCR. The therapeutic efficacy of lead candidates was evaluated by histopathological analysis, immunofluorescence, and molecular readouts of inflammation and tissue injury in a murine COPD model induced by long-term inhalation of a mixture of Pb and Cd (Pb/Cd). ASO safety was further assessed both in vitro and in vivo, including acute and chronic toxicity studies. RESULTS: Ninj1 expression was markedly upregulated in the lungs of mice following exposure to TS components (NNK and BaP), particulate matter (PM), or Pb/Cd. Intratracheal delivery of Ninj1-targeting ASO attenuated hallmark COPD-associated features, including alveolar airspace enlargement, mucus hypersecretion, oxidative stress, matrix metalloproteinase activity, and fibrotic lesions, without evidence of overt systemic toxicity. CONCLUSIONS: These findings establish Ninj1 as a critical mediator of chronic lung inflammation and a translationally relevant therapeutic target, highlighting Ninj1-directed ASO therapy as a promising strategy for the treatment of environmental toxicant-induced respiratory diseases.
Sim et al. (Tue,) studied this question.