PAF acetylhydrolase gene polymorphisms and asthma severity.
This review describes the current understanding of the contributions of genetic alterations in platelet-activating factor (PAF) acetylhydrolase to the pathogenesis of asthma. A variety of in vitro and in vivo studies, performed by multiple laboratories, suggest that the lipid substrates of this enzyme, PAF and oxidised derivatives of phosphatidylcholines, play important roles as causative factors in many diseases including asthma. PAF acetylhydrolase inactivates PAF and oxidatively-fragmented lipids thus providing a mechanism to prevent their pro-inflammatory effects. Since it is a most unusual protein, the biochemical, structural and functional characteristics of PAF acetylhydrolase continue to be unravelled. First, the ability of this enzyme to inactivate pro-inflammatory lipid mediators is modulated by its association with lipoproteins and by its susceptibility to oxidative inactivation. Second, mediators of inflammation, such as the substrates for PAF acetylhydrolase, alter expression of the protein at the transcriptional level. Third, naturally-occurring variants of PAF acetylhydrolase have catalytic properties different from those exhibited by the most common form of this protein. Thus, a variety of factors, including genetics, contribute to determine the biological level of lipid substrates known to act as mediators of asthma and other diseases. Here, I summarise key studies that implicate PAF and related molecules as important mediators in the pathogenesis of asthma. Next, I describe clinical findings that are consistent with a role of PAF acetylhydrolase as a modulator of asthma. Third, I focus on the biochemical effects associated with naturally-occurring mutations and polymorphisms in the PAF acetylhydrolase gene and the incidence of these genetic variations in populations of asthmatic subjects. Finally, I present my views on the future of this emerging field and the potential utility of performing additional studies aimed at further characterising the contribution of PAF acetylhydrolase to the pathogenesis of a complex syndrome generally recognised as a multifactorial and heterogeneous disease.
Stafforini
D M
DM
Huntsman Cancer Institute, 2000 Circle of Hope, University of Utah, Salt Lake City, UT 84112-5550, USA. diana.stafforini@hci.utah.edu
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D001249:Asthma / Q000201:enzymology / Q000209:etiology / Q000235:genetics*; D008040:Genetic Linkage; D006801:Humans; D010741:Phospholipases A / Q000172:deficiency / Q000235:genetics*; D010972:Platelet Activating Factor / Q000032:analysis / Q000502:physiology; D010980:Platelet Membrane Glycoproteins / Q000032:analysis / Q000502:physiology; D011110:Polymorphism, Genetic; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled
D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor; D010741:Phospholipases A; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase