Protective effect of beraprost sodium, a stable prostacyclin analog, in the development of cigarette smoke extract-induced emphysema

1 First Department of Medicine, Shinshu University School of Medicine, Matsumoto, Nagano, Japan; 2 Division of Respiratory Disease, Department of Internal Medicine, The Second Xiangya Hospital, Central-South University, Changsha, Hunan, China; 3 Victoria Johnson Center for Obstructive Lung Diseases, Virginia Commonwealth University, Richmond, Virginia Submitted 9 April 2008 ; accepted in final form 31 January 2009 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 determined whether a synthetic stable prostacyclin analog, beraprost sodium (BPS), attenuates the development of CSE-induced emphysema and elucidated the molecular mechanisms involved in its effect. Sprague-Dawley rats were treated with BPS and injected with CSE once a week for 3 wk. We measured the DNA damage of cells, the expression of caspase-3, and the activity of matrix metalloproteinase (MMP)-2 and MMP-9. We also analyzed TNF and IL-1β 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-1β 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. apoptosis; inflammation; rat; oxidative stress; matrix metalloproteinase Address for reprint requests and other correspondence: M. Hanaoka, First Dept. of Medicine, Shinshu Univ. School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan (e-mail: masayuki{at}shinshu-u.ac.jp )