Lipopolysaccharide and the lung: a story of love and hate

Lipopolysaccharide (LPS) is a major component of the outer membrane of Gram-negative bacteria. LPS is one of the most potent microbial inducers of inflammation and is responsible for many of the deleterious effects of pulmonary infections. In contrast, surfaces of the body are constantly exposed to small amounts of LPS. This interaction appears to stimulate more beneficial, protective mechanisms. Overall, the interactions between LPS and the body are important; however, factors that determine the nature of this response are not known. LPS is a prototypical pathogen associated molecular pattern (PAMP), a term that was introduced by Janeway and Medzhitov 1, which describes structurally conserved molecules of microorganisms. PAMPs bind to receptors of the innate immune system, consequently called pattern recognition receptors (PRRs). In 1996, the Drosophila protein Toll was shown to be required for flies to mount an effective immune response against the fungus Aspergillus fumigatus . In 1998, toll like receptor (TLR)4 was positionally identified as the LPS receptor and found to be required for mice to effectively respond to Gram-negative bacteria. These findings have guided the field of (innate) immunity over the last few years. Thirteen mammalian TLR analogues have been identified and functionally linked to various processes, ranging from inflammation and infection, to arthrosclerosis and sterile inflammation 2. In the lung, TLR4 is expressed by several different cell types, including professional host defence (dendritic cells, macrophages) and structural (endothelial and epithelial cells) cells. Animal models and patient studies have proved that TLR4 contributes significantly to the response to inhaled LPS 3, …