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Published ahead of print on August 14, 2003, doi:10.1165/rcmb.2003-0263OC

Am. J. Respir. Cell Mol. Biol., Volume 30, Number 2, February 2004, 228-232

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Submitted on July 11, 2003
Revised on August 12, 2003

Surfactant Blocks LPS Signaling by Inhibiting both MAP and I{kappa}B Kinases in Human Alveolar Macrophages

Baisakhi Raychaudhuri1, Susamma Abraham1, Tracey L Bonfield1, Anagha Malur1, Amitabha Deb2, Joseph A DiDonato2, Mani S Kavuru1, and Mary Jane Thomassen1*

1 Department of Pulmonary and Critical Care Medicine, Cleveland Clinic Foundation, Cleveland, OH, USA, 2 Department of Cancer Biology, Cleveland Clinic Foundation, Cleveland, OH, USA

* To whom correspondence should be addressed. E-mail: thomasm{at}ccf.org.

Surfactant plays an important role in lung homeostasis and is also involved in maintaining innate immunity within the lung. Lipopolysaccharide (LPS) from gram-negative bacteria is known to elicit acute proinflammatory responses in lung diseases such as acute respiratory distress syndrome (ARDS) and pneumonia, among others. Our previous studies demonstrated that the clinically used, natural surfactant product, Survanta inhibited proinflammatory cytokine secretion from LPS-stimulated human alveolar macrophages. Here we investigated the effect of Survanta on MAP and I{kappa}B kinases. Survanta blocked LPS-induced activation of nuclear factor kappa B (NF-{kappa}B), a key regulatory transcription factor involved in cytokine production, by preventing phosphorylation of I{kappa}B {alpha}, and its subsequent degradation. I{kappa}B is phosphorylated by specific kinases (IKK) before degradation. Survanta inhibited activity of both alpha and beta subunits of IKK, thereby delaying the phosphorylation of I{kappa}B. Interestingly, IKK-{alpha} is predominant in alveolar macrophages whereas IKK-{beta} predominates in monocytes. Survanta also inhibited extra cellular signal regulated kinase (ERK) and p38 MAP kinase activity induced by LPS. Data are the first to show that surfactant may regulate lung homeostasis in part by inhibiting pro-inflammatory cytokine production through reduction of IKK and MAPK activity.




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