Chronic inflammation, imbalance of proteolytic and anti-proteolytic activities, oxidative stress and apoptosis of lung structural cells contribute to the pathogenesis of COPD. Prostacyclin protects cells against apoptosis, has anti-inflammatory properties, partially prevents cigarette smoke extract (CSE)-induced apoptosis of the pulmonary endothelium and thus may be relevant in the pathogenesis of emphysema. We determine whether a synthetic stable prostacyclin analogue, beraprost sodium (BPS), attenuates the development of CSE-induced emphysema and elucidate the molecular mechanisms involved in its effect. Sprague-Dawley rats were treated with BPS and injected with CSE once a week for three weeks. We measured the DNA damage of cells, the expression of caspase-3 and the activity of MMP-2 and MMP-9. We also analyzed TNF- and IL-1 concentrations and the serum antioxidant activity. BPS prevented the development of CSE-induced emphysema, resulting in significant attenuation in alveolar enlargement and pulmonary parenchymal destruction. BPS inhibited pulmonary apoptosis and induction of MMP-2 and MMP-9 activity. Moreover, the protective effect of BPS was associated with a reduction of the expression of proinflammatory cytokines including TNF- and IL-1 and a normalized biological oxidant activity. BPS introduces all these events probably by activating cAMP signaling through acting specific prostacyclin receptors. In conclusion, BPS protects against the development of CSE-induced emphysema by attenuating apoptosis, inhibiting proteolytic enzyme activity, reducing inflammatory cytokine levels and augmenting antioxidant activity. BPS may potentially represent a new therapeutic option in the prevention of emphysema in humans in prospect.