Eicosanoids in Cystic Fibrosis
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《新英格兰医药杂志》
To the Editor: According to the report by Freedman et al. (Feb. 5 issue),1 the median ratio of arachidonic acid to docosahexaenoic acid in patients with cystic fibrosis was higher than that in healthy subjects. Because linoleic acid is metabolized to arachidonic acid in humans, a deficiency in linoleic acid might cause increased metabolism of arachidonic acid. In cystic fibrosis cells expressing the F508 defect in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), the conversion of linoleic acid to arachidonic acid increased significantly as compared with that in cystic fibrosis cells transfected with the CFTR gene.2 The decreased level of docosahexaenoic acid in cystic fibrosis could be explained by the primary defect in docosahexaenoic acid biosynthesis, because administration of -linolenic acid resulted in a further decrease in the level of docosahexaenoic acid in CFTR knockout mice but not in wild-type mice.3 This result suggests that there might be a block in the biosynthesis of docosahexaenoic acid.
Yujiro Kida, M.D., Ph.D.
Tokyo Metropolitan Komagome Hospital
Tokyo 113-8677, Japan
References
Freedman SD, Blanco PG, Zaman MM, et al. Association of cystic fibrosis with abnormalities in fatty acid metabolism. N Engl J Med 2004;350:560-569.
Bhura-Bandali FN, Suh M, Man SFP, Clandinin MT. The F508 mutation in the cystic fibrosis transmembrane regulator alters control of essential fatty acid utilization in epithelial cells. J Nutr 2000;130:2870-2875.
Freedman SD, Katz MH, Parker EM, Laposata M, Urman MY, Alvarez JG. A membrane lipid imbalance plays a role in the phenotypic expression of cystic fibrosis in cftr -/- mice. Proc Natl Acad Sci U S A 1999;96:13995-14000.
To the Editor: Freedman et al. report an elevated ratio of arachidonic to docosahexaenoic acid in nasal-biopsy and rectal-biopsy specimens from patients with cystic fibrosis. These findings are consistent with the results of previous studies suggesting an increased susceptibility to stimulation of cytoplasmic phospholipase A2 in cell lines carrying the F508 mutation.1 Cytoplasmic phospholipase A2 initiates the arachidonic acid cascade by releasing arachidonic acid from phospholipids, leading to the generation of a wide range of bioactive eicosanoids that may contribute to inflammation in cystic fibrosis.2
Evidence of the involvement of this pathway in the pathophysiology of cystic fibrosis must shift the focus of our attention toward the development of phospholipase A2–selective inhibitory agents as a primary target of future therapy for cystic fibrosis.
Bernhard Steger, M.B., B.S.
Hans Peter Colvin, M.B., B.S.
University of Innsbruck Medical School
6020 Innsbruck, Austria
csab8199@uibk.ac.at
References
Berguerand M, Klapisz E, Thomas G, et al. Differential stimulation of cytosolic phospholipase A2 by bradykinin in human cystic fibrosis cell lines. Am J Respir Cell Mol Biol 1997;17:481-490.
Strandvik B. Fatty acid metabolism in cystic fibrosis. N Engl J Med 2004;350:605-607.
The authors reply: Dr. Kida points out that the alteration in fatty acid metabolism that leads to a low level of docosahexaenoic acid (22:6n–3) in patients with cystic fibrosis1 may be explained by a primary defect in docosahexaenoic acid biosynthesis. We have stated, in agreement with Dr. Kida, that the mechanism in patients with cystic fibrosis that produces the changes in fatty acids, such as the reductions in docosahexaenoic acid and linoleic acid levels,2,3 has yet to be determined.1,4 In studies we performed in CFTR knockout mice, eicosapentaenoic acid (a metabolic precursor of docosahexaenoic acid) did not correct the phenotype.4 This finding lends support to Dr. Kida's suggested mechanism of impaired synthesis of docosahexaenoic acid. Experiments to assess amelioration of the cystic fibrosis phenotype in knockout mice by supplementation with the n–3 fatty acids located between eicosapentaenoic acid and docosahexaenoic acid in the n–3 fatty acid pathway (22:5n–3, 24:5n–3, and 24:6n–3) have not yet been performed.
Drs. Steger and Colvin suggest that the alterations in fatty acid metabolism that we observed in patients with cystic fibrosis may be a result of increased activity of cytoplasmic phospholipase A2. This suggestion is consistent with data reported by Carlstedt-Duke et al.5 They found that there is increased release of radiolabeled arachidonate from the lymphocyte phospholipids of patients with cystic fibrosis relative to those of normal controls. The implication of these studies is that the arachidonate released from phospholipids may subsequently be converted into proinflammatory eicosanoids.
Michael Laposata, M.D., Ph.D.
Massachusetts General Hospital
Boston, MA 02114
Brian P. O'Sullivan, M.D.
UMass Memorial Health Care
Worcester, MA 01605
Steven D. Freedman, M.D., Ph.D.
Beth Israel Deaconess Medical Center
Boston, MA 02215
sfreedma@caregroup.harvard.edu
References
Freedman SD, Blanco PG, Zaman MM, et al. Association of cystic fibrosis with abnormalities in fatty acid metabolism. N Engl J Med 2004;350:560-569.
Bhura-Bandali FN, Suh M, Man SFP, Clandinin MT. The F508 mutation in the cystic fibrosis transmembrane regulator alters control of essential fatty acid utilization in epithelial cells. J Nutr 2000;130:2870-2875.
Strandvik B, Gronowitz E, Enlund F, Martinsson T, Wahlstrom J. Essential fatty acid deficiency in relation to genotype in patients with cystic fibrosis. J Pediatr 2001;139:650-655.
Freedman SD, Katz MH, Parker EM, Laposata M, Urman MY, Alvarez JG. A membrane lipid imbalance plays a role in the phenotypic expression of cystic fibrosis in cftr -/- mice. Proc Natl Acad Sci U S A 1999;96:13995-14000.
Carlstedt-Duke J, Bronnegard M, Strandvik B. Pathological regulation of arachidonic acid release in cystic fibrosis: the putative basic defect. Proc Natl Acad Sci U S A 1986;83:9202-9206.
Yujiro Kida, M.D., Ph.D.
Tokyo Metropolitan Komagome Hospital
Tokyo 113-8677, Japan
References
Freedman SD, Blanco PG, Zaman MM, et al. Association of cystic fibrosis with abnormalities in fatty acid metabolism. N Engl J Med 2004;350:560-569.
Bhura-Bandali FN, Suh M, Man SFP, Clandinin MT. The F508 mutation in the cystic fibrosis transmembrane regulator alters control of essential fatty acid utilization in epithelial cells. J Nutr 2000;130:2870-2875.
Freedman SD, Katz MH, Parker EM, Laposata M, Urman MY, Alvarez JG. A membrane lipid imbalance plays a role in the phenotypic expression of cystic fibrosis in cftr -/- mice. Proc Natl Acad Sci U S A 1999;96:13995-14000.
To the Editor: Freedman et al. report an elevated ratio of arachidonic to docosahexaenoic acid in nasal-biopsy and rectal-biopsy specimens from patients with cystic fibrosis. These findings are consistent with the results of previous studies suggesting an increased susceptibility to stimulation of cytoplasmic phospholipase A2 in cell lines carrying the F508 mutation.1 Cytoplasmic phospholipase A2 initiates the arachidonic acid cascade by releasing arachidonic acid from phospholipids, leading to the generation of a wide range of bioactive eicosanoids that may contribute to inflammation in cystic fibrosis.2
Evidence of the involvement of this pathway in the pathophysiology of cystic fibrosis must shift the focus of our attention toward the development of phospholipase A2–selective inhibitory agents as a primary target of future therapy for cystic fibrosis.
Bernhard Steger, M.B., B.S.
Hans Peter Colvin, M.B., B.S.
University of Innsbruck Medical School
6020 Innsbruck, Austria
csab8199@uibk.ac.at
References
Berguerand M, Klapisz E, Thomas G, et al. Differential stimulation of cytosolic phospholipase A2 by bradykinin in human cystic fibrosis cell lines. Am J Respir Cell Mol Biol 1997;17:481-490.
Strandvik B. Fatty acid metabolism in cystic fibrosis. N Engl J Med 2004;350:605-607.
The authors reply: Dr. Kida points out that the alteration in fatty acid metabolism that leads to a low level of docosahexaenoic acid (22:6n–3) in patients with cystic fibrosis1 may be explained by a primary defect in docosahexaenoic acid biosynthesis. We have stated, in agreement with Dr. Kida, that the mechanism in patients with cystic fibrosis that produces the changes in fatty acids, such as the reductions in docosahexaenoic acid and linoleic acid levels,2,3 has yet to be determined.1,4 In studies we performed in CFTR knockout mice, eicosapentaenoic acid (a metabolic precursor of docosahexaenoic acid) did not correct the phenotype.4 This finding lends support to Dr. Kida's suggested mechanism of impaired synthesis of docosahexaenoic acid. Experiments to assess amelioration of the cystic fibrosis phenotype in knockout mice by supplementation with the n–3 fatty acids located between eicosapentaenoic acid and docosahexaenoic acid in the n–3 fatty acid pathway (22:5n–3, 24:5n–3, and 24:6n–3) have not yet been performed.
Drs. Steger and Colvin suggest that the alterations in fatty acid metabolism that we observed in patients with cystic fibrosis may be a result of increased activity of cytoplasmic phospholipase A2. This suggestion is consistent with data reported by Carlstedt-Duke et al.5 They found that there is increased release of radiolabeled arachidonate from the lymphocyte phospholipids of patients with cystic fibrosis relative to those of normal controls. The implication of these studies is that the arachidonate released from phospholipids may subsequently be converted into proinflammatory eicosanoids.
Michael Laposata, M.D., Ph.D.
Massachusetts General Hospital
Boston, MA 02114
Brian P. O'Sullivan, M.D.
UMass Memorial Health Care
Worcester, MA 01605
Steven D. Freedman, M.D., Ph.D.
Beth Israel Deaconess Medical Center
Boston, MA 02215
sfreedma@caregroup.harvard.edu
References
Freedman SD, Blanco PG, Zaman MM, et al. Association of cystic fibrosis with abnormalities in fatty acid metabolism. N Engl J Med 2004;350:560-569.
Bhura-Bandali FN, Suh M, Man SFP, Clandinin MT. The F508 mutation in the cystic fibrosis transmembrane regulator alters control of essential fatty acid utilization in epithelial cells. J Nutr 2000;130:2870-2875.
Strandvik B, Gronowitz E, Enlund F, Martinsson T, Wahlstrom J. Essential fatty acid deficiency in relation to genotype in patients with cystic fibrosis. J Pediatr 2001;139:650-655.
Freedman SD, Katz MH, Parker EM, Laposata M, Urman MY, Alvarez JG. A membrane lipid imbalance plays a role in the phenotypic expression of cystic fibrosis in cftr -/- mice. Proc Natl Acad Sci U S A 1999;96:13995-14000.
Carlstedt-Duke J, Bronnegard M, Strandvik B. Pathological regulation of arachidonic acid release in cystic fibrosis: the putative basic defect. Proc Natl Acad Sci U S A 1986;83:9202-9206.