Chronic obstructive pulmonary disease (
COPD) is a debilitating
lung disease with no effective treatment that can reduce mortality or slow the
disease progression.
COPD is the third leading cause of global death and is characterized by airflow limitations due to
chronic bronchitis and alveolar damage/
emphysema. Chronic cigarette
smoke (CS) exposure damages airway and alveolar epithelium and remains a major risk factor for the pathogenesis of
COPD. We found that the expression of
caveolin-1, a
tumor suppressor protein; p53; and
plasminogen activator inhibitor-1 (PAI-1), one of the downstream targets of p53, was markedly increased in airway epithelial cells (AECs) as well as in type II alveolar epithelial (AT2) cells from the lungs of patients with
COPD or wild-type mice with CS-induced
lung injury (CS-LI). Moreover, p53- and PAI-1-deficient mice resisted CS-LI. Furthermore, treatment of AECs, AT2 cells, or lung tissue slices from patients with
COPD or mice with CS-LI with a seven
amino acid caveolin-1 scaffolding domain peptide (CSP7) reduced mucus hypersecretion in AECs and improved AT2 cell viability. Notably, induction of
PAI-1 expression via increased
caveolin-1 and p53 contributed to mucous cell
metaplasia and mucus hypersecretion in AECs, and reduced AT2 viability, due to increased senescence and apoptosis, which was abrogated by CSP7. In addition, treatment of wild-type mice having CS-LI with CSP7 by
intraperitoneal injection or nebulization via airways attenuated mucus hypersecretion, alveolar injury, and significantly improved lung function. This study validates the potential therapeutic role of CSP7 for treating CS-LI and
COPD. NEW & NOTEWORTHY Chronic cigarette
smoke (CS) exposure remains a major risk factor for the pathogenesis of
COPD, a debilitating disease with no effective treatment. Increased
caveolin-1 mediated induction of p53 and downstream
plasminogen activator inhibitor-1 (PAI-1) expression contributes to CS-induced airway mucus hypersecretion and alveolar wall damage. This is reversed by
caveolin-1 scaffolding domain peptide (CSP7) in preclinical models, suggesting the therapeutic potential of CSP7 for treating CS-induced
lung injury (CS-LI) and
COPD.