The Relationship Of Platelet Activating Factor Acetylhydrolase Activity And Single Nucleotide Polymorphism In Its Gene With Psoriasis

Platelet-activating factor (PAF,1-O-alkyl-2-acetylsn-glycero-3-phosphocholine) is a biologically active phospholipid with diverse potent biological effects. It is associated with the pathology of several human diseases, particularly allergy and inflammation, affecting the respiratory, vascular, digestive and reproductive systems. Its accumulation is tightly regulated at the synthetic and degradative levels to avoid the inappropriately high accumulation of PAF observed in many diseases,such as systemic lupus erythematosus ,allergic diseases and septic shock and so on.PAF is degraded to inactive products by hydrolysis of the acetyl group at the sn -2 position, to produce the biologically inactive products lyso-PAF and acetate. This reaction is catalyzed by PAF acetylhydrolase, a calcium-independent phospholipase A2 specific for hydrolysis of phospholipids containing short and/or oxidized chains at the sn -2 position of the glycerol backbone. There are two type of PAF-AH,namely plasma PAF-AH and cellular PAF-AH .The latter have three isoenzymes: type â… a ,typeâ… b and type â…¡. The â… b subunit is 99% homologous to a product of the LIS1 gene, mutations of which cause type I lissencephaly.The activity of PAF-AH was first described in 1980. Subsequently, Blank and colleagues reported that this enzyme is widely distributed in mammalian tissues and blood and that it is specific for deacetylation of phospholipids. Miwa et al. reported that 4% of the Japanese population is deficient in PAF acetylhydrolase activity in plasma, and that the prevalence of deficiency of the enzyme is higher in children with severe asthma. It suggested that PAF-AH plays an important role in the inflammatory reaction. The gene for the plasmatic PAF-AH has been mapped to chromosome 6p21.2-p12, consisting of 12 exons,originally assigned as the human leukocyte antigen region. The predicted amino acid sequence of the plasma form of PAF-AH contains a Gly-Xaa-Ser- Xaa-Gly motif characteristic of lipases and esterases. The serine residue in this conserved motif is essential for activity and it explains the ability of serine esterase inhibitors to abolish enzymatic activity. It is interesting that PAF-AH gene is in the region which is high sensitive to asthma and atopic dermatitis. To determine the molecular basis of inherited PAF-AH deficiency, Stafforini et al amplified all coding exons in the PAF acetylhydrolase gene using DNA isolated from subjects with normal and deficient levels of PAF-AH activity. They identified two point mutation, Val279Phe and Gln281Arg near the active site of PAF-AH that is related to deficency of plasma activity in Japanese subjects. This mutation, Val279Phe, as a heterozygous trait is present in 27%,as well as a homozygote trait in 4%, in the Japanese population. The mutant alle is higher in the patients with asthma than that in the health population. In a murine asthma model, Henderson examined the anti-inflammatory activities of recombinant human (rPAF-AH). In this model, mice sensitized to ovalbumin by i.p. and intranasal (i.n.) routes are challenged with the allergen by i.n. administration. The ovalbumin challenge elicits an eosinophil infiltration into the lungs with widespread mucus occlusion of the airways and results in bronchial hyperreactivity. The administration of rPAF-AH had a marked effect on late-phase pulmonary inflammation, which included a significant reduction in airway eosinophil infiltration, mucus hypersecretion, and airway hyperreactivity in response to methacholine challenge. These studies demonstrate that elevating plasma levels of PAF-AH through the administration of rPAF-AH is effective in blocking the late-phase pulmonary inflammation that occurs in this murine allergen-challenge asthma model. These results suggest that rPAF-AH may have therapeutic effects in patients with allergic airway inflammation. In recent,it is reported that Val279Phe SNPs is associated with shock and nonfamilial hypertrophic cardiomyopathy. Two loss-of-function mutations of PAF-AH, Val279Phe and Gln281Arg, associate...