Impact of intranasal cigarette smoke exposure on murine peripheral immune responses and lung pathology

Chronic obstructive pulmonary disease (COPD) is driven primarily by cigarette smoke exposure, yet modelling its immunopathogenesis in mice is complicated by systemic stress and welfare concerns associated with conventional exposure models. Here, we employ a refined intranasal cigarette smoke extract (CSE) model to examine pulmonary pathology and peripheral immune responses in male and female C57BL/6J mice. Repeated intranasal CSE exposure over 12 weeks was well tolerated and induced dose-dependent pulmonary neutrophilia, airway remodelling, and collagen deposition, with more pronounced pathology observed in female mice at higher exposure levels. In contrast, longitudinal multiparametric flow cytometric analysis revealed no consistent dose-dependent alterations in peripheral immune cell composition or activation, as confirmed by both conventional gating and unbiased clustering approaches. These findings demonstrate that COPD-like lung pathology can arise in the absence of overt systemic immune disruption and highlight the importance of lung inflammatory processes in disease development. This refined intranasal model provides a welfare-conscious platform for studying pulmonary immunopathology in COPD.