HO-1-Enriched Lung-Derived Exosomes Mediate Cognitive Impairment in a Mice Model of COPD Exacerbation

This study aimed to elucidate the impact of HO-1 on cognitive function in chronic obstructive pulmonary disease (COPD) exacerbation mice and uncover the bridging role of exosomes in the interorgan transport of HO-1 along the "lung-brain" axis, providing novel insights into COPD-associated cognitive dysfunction.

HO-1(-/-) and wild-type mice were subjected to COPD exacerbation modeling through cigarette smoke and LPS exposure. Four groups were divided: (A) HO-1(+/+) mice; (B) HO-1(+/+) COPD exacerbation mice; (C) HO-1(-/-) mice; and (D) HO-1(-/-) COPD exacerbation mice. Cognitive function was assessed using the Morris water maze. Lung-derived exosomal HO-1 was quantified by Western blot. Fluorescently labeled exosomes from Groups A/B were injected into HO-1(-/-) mice via tail vein, generating four new cohorts: Group I: HO-1(+/+) mice injected with PBS; Group II: HO-1(-/-) mice injected with PBS; Group III: HO-1(-/-) mice injected with exosome (Exos) from Group A; Group IV: HO-1(-/-) mice injected with Exos from Group B; Exos biodistribution was tracked via in vivo imaging, followed by cognitive reassessment and HO-1 quantification.

Groups B/D showed reduced target quadrant dwell time versus Groups A/C, and Group B exhibited longer target quadrant dwell time than Group D. This shows that COPD exacerbation mice had cognitive decline, which was exacerbated by HO-1 deficiency. Group B exhibited higher HO-1 expression in lung exosomes than Group A. Injected exosomes accumulated preferentially in lungs over brain; Group IV displayed worse cognitive impairment than Group III.

COPD exacerbation mice exhibit cognitive decline regardless of HO-1 expression status, but HO-1 knockout COPD exacerbation mice demonstrate more pronounced cognitive impairment. In COPD exacerbation mice, HO-1 expression is elevated in lung-derived exosomes. Cross-organ transduction experiments confirm that HO-1 can be transported via Exos and mediate cognitive dysfunction in COPD exacerbation mice. Thus, HO-1 exerts a concentration-dependent dual effect on brain function: protective at physiological levels yet detrimental when in excess.