Dynamic regulation of cardiolipin by the lipid pump Atp8b1 determines the severity of lung injury in experimental pneumonia

Ray, N.B. et al. 2010. Nat. Med.16, 1120-1127.

Speaker: Zhou Yu (周妤)                                               Time: 13:00~14:00, Dec. 29, 2010

Commentator: Dr. Ching-Hao Teng (鄧景浩老師)      Place: Room 601

Abstract:

Pneumonia due to infection is an important cause of death worldwide. There has been an overreliance on the use of broad-spectrum antibiotics in severe infection, causing the emergence of multidrug resistant bacterial strains. Studies on the pathophysiological mechanisms of bacterial pneumonia may lead to development of non-antibiotic therapeutic strategies. The maintenance of efficient gas exchange, the main physiological function of the mammalian lung, is essential for life. Normal gas exchange in the mammalian lung requires the production of pulmonary surfactant, a mixture of phospholipids and proteins produced by type II alveolar cells that reduce surface tension in the alveoli. In this study, the authors discovered the abundance of cardiolipin in lung fluid is regulated by Atp8b1, which effectively binds and internalizes cardiolipin in lung epithelia. Recently, mutations in a member of the ATP-binding cassette family of transporters, ABCA3, have been shown to result in fatal surfactant deficiency in neonates. Individuals with mutations in ATP8b1, which is a member of this protein family and is expressed in bile canaliculated to transport bile acid, develop progressive familial intrahepatic cholestasis type 1 or Byler disease, gastrointestinal tract diseases and also have an increase risk for pneumonia. The results show that cardiolipin concentrations are elevated in the lung fluid of individuals with pneumonia and that it is a highly potent surfactant inhibitor that disrupts lung structure and function. Furthermore, the authors showed that administration of a cardiolipin binding domain peptide of Atp8b1 in mice reduced bacterial-induced lung injury and improved survival. Taken together, these findings open the door for new therapeutic strategies directed at modulating the abundance or molecular interactions of cardiolipin in pneumonia.

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