Relation between defective regulation of arachidonic acid release and symptoms in cystic fibrosis.
A hypothesis is formed about the basic defect in CF based on the findings of 1) a defective inhibition of AA release by dexamethasone stimulation of lymphocytes from patients with CF, probably due to a defect in or absence of lipocortin and 2) the essential fatty acid deficiency (EFAD) in CF reported by different authors for 25 years. Both in lymphocytes and fibroblasts from patients with CF increased AA release has been demonstrated. AA, substrate for the eicosanoid system (prostaglandins, leukotrienes, hydroxyeicosatetraenoic acids, thromboxanes), has been shown to increase mucus release, influence chloride transport and the stimulus-secretion coupling (Ca++ balance), all factors suggested as basic defects in CF. The increased release of AA might explain the development of EFAD, since AA is synthesized from linoleic acid. In animals EFAD gives rise to symptoms similar to those in CF, e.g. defect Na transport, liver steatosis, increased caloric need, disturbed insulin release, increased bacterial colonization of airways, and decreased immune response. Regular supplementation with fat emulsion (Intralipid) to CF patients normalizes the renal Na transport and prevents liver steatosis. We suggest that the basic defect in CF is a defect in or absence of lipocortin, causing an increased release of AA, which regulates synthesis in the eicosanoid system. An increase of the products in this system gives rise to the basic signs and symptoms of CF. The resulting EFAD is dependent on the rate of AA turnover and could explain most of the clinical symptoms and the progression of the disease.
Strandvik
B
B
Dept. of Pediatrics, Karolinska Institutet, Huddinge University Hospital, Sweden.
Brönnegård
M
M
Gilljam
H
H
Carlstedt-Duke
J
J
D017302:Annexins; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism*; D003550:Cystic Fibrosis / Q000378:metabolism*; D005228:Fatty Acids, Essential / Q000172:deficiency; D005347:Fibroblasts / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D007473:Ion Channels / Q000378:metabolism; D008214:Lymphocytes / Q000378:metabolism; D010740:Phospholipases / Q000037:antagonists & inhibitors
D017302:Annexins; D001095:Arachidonic Acids; D005228:Fatty Acids, Essential; D006023:Glycoproteins; D007473:Ion Channels; D016718:Arachidonic Acid; D010740:Phospholipases