Chest -- eLetters for Mickleborough et al., 129 (1) 39-49

HOME

HELP

FEEDBACK

SUBSCRIPTIONS

ARCHIVE

QUICK SEARCH:

[advanced]

	Author:		Keyword(s):
Year:		Vol:		Page:

Guest Access | Sign In via User Name/Password

Electronic Letters to:

ASTHMA:
Timothy D. Mickleborough, Martin R. Lindley, Alina A. Ionescu, and Alyce D. Fly
Protective Effect of Fish Oil Supplementation on Exercise-Induced Bronchoconstriction in Asthma
Chest 2006; 129: 39-49 [Abstract] [Full text] [PDF]

eLetters: Submit a response to this article

Electronic letters published:

Untitled: Andrew Charig (5 March 2006)

Biological mechanisms underpinning the beneficial role of fish oil on inflammation: Timothy D Mickleborough (5 April 2006)

Untitled 5 March 2006

Andrew Charig,
Chemist
Church & Dwight Co Inc
Send letter to journal:
Re: this article

ACharig{at}hotmail.com Andrew Charig

I will believe it when I hear the mechanism explained. What have eicosapentaenoic and docohexaenoic acid to do with the inflammation process, especially given that they are rapidly catabolized?
The empirical data is unconvincing without theoretical support.

Biological mechanisms underpinning the beneficial role of fish oil on inflammation 5 April 2006

Timothy D Mickleborough,
Asst Professor
Indiana University
Send letter to journal:
Re: Biological mechanisms underpinning the beneficial role of fish oil on inflammation

tmickleb{at}indiana.edu Timothy D Mickleborough

We would like to thank Andrew Charig for his recent e-letter asking about the proposed mechanism whereby eicosapentaenoic acid (EPA) and docohexaenoic acid (DHA), found in fish oil, reduce inflammation. In two recent studies from our laboratory we have found that fish oil reduces airway inflammation and blunts the post-exercise bronchoconstriction in elite athletes and asthmatic subjects (1, 2).
Molecules with important roles in inflammation include proinflammatory leukotrienes and prostaglandins. These are produced from conversion of the omega-6 fatty acid arachidonic acid (AA), via the enzymes cyclooxygenase (COX) and lipoxygenase. In contrast, it has long been known that omega-3 fatty acids enriched in fish oils have beneficial anti-inflammatory properties (3). Similar to AA, the omega-3 fatty acids (EPA) and DHA are substrates for COX and lipoxygenase. Therefore, it has been proposed that EPA and DHA may suppress the pro-inflammatory activities of AA and its metabolites (eicosanoids and cytokines) via both competition for the same enzymatic pathway, and the induction of products with lesser inflammatory activity (4-8). One EPA derivative termed Resolvin E1 (RvE1) has received recent attention, and the discovery of its receptor provides evidence for a novel mechanism underlying its anti- inflammatory activity.
RvE1 was first described in mouse exudates during the resolution phase of inflammation, and is reportedly synthesized in human cells from EPA by a novel transcellular mechanism (9). In this proposed pathway, EPA is converted to 18R-Hydroxy-EPA by aspirin-suppressed COX-2 in endothelial cells. This precursor is then transferred to adjacent leukocytes where it is transformed into RvE1 in the presence of 5-lipoxygenase. Administration of RvE1 suppresses leukocyte infiltration, and proinflammatory cytokine and chemokine production in models of colitis and peritonitis (10). A new report by Arita et al.(11) suggests that these anti-inflammatory activities may occur via a mechanism that includes RvE1 binding to the cell surface receptor Chem R23.
Chem R23 is a 7 transmembrane G protein-coupled receptor highly expressed in monocyte-derived antigen-presenting cells (APCs), and to a lesser extent neutrophils and lymphocytes (11). Radiolabeled RvE1 binds specifically to Chem R23-transfected CHO cells, but not to mock- transfected controls. It stimulates pertussis toxin-sensitive MAP kinase phosphorylation and NFkB inhibition in Chem R23-transfected HEK cells, indicating a necessary activation of the Gi/o subtype of G protein. Administration of RvE1 suppresses both pathogen-induced dendritic cell IL- 12 production and trafficking in spleen. The effects on IL-12 production are inhibited by Chem R23 siRNA, providing strong evidence that RvE1 acts through the Chem R23 receptor (11).
Interestingly, Chem R23 is also a peptide receptor. It binds to the protein Chemerin, a distant member of the Cystatin family and mediator of APC chemoattraction (11). Competition studies suggest that both RvE1 and Chemerin bind to a similar region of Chem R23, and yet exhibit differences in their effects on cells. G protein activation by Chemerin is approximately 3 fold that of RvE1, while RvE1 is approximately 10 fold more potent in its ability to block TNF-a-induced NFkB inhibition(11). It also appears that Chemerin acts as an inducer of cell migration, while RvE1 has negative effects on this activity (10). The mechanisms are unclear, although it has been proposed that G protein-coupled receptors might adopt different conformations depending on the ligand, thus resulting in different signaling properties and activities (9).
Interestingly, Li and coworkers (12) recently demonstrated that EPA and DHA down-regulate LPS-induced activation of nuclear factor (NF)- kappa(�)B via a peroxisome proliferator-activated receptor (PPAR)-�- dependent pathway in human kidney cells. These results suggest that PPAR-� activation by EPA and DHA may be one of the underlying mechanisms for the beneficial effects of fish oil.
Omega-3-fatty acids therefore seem to interfere with inflammatory signal transduction processes and are thus capable of blunting hyper- inflammation. In addition, the identification of a specific receptor mediating the anti-inflammatory activities of fish oil-derived omega-3 fatty acids or their derivatives could result in novel therapeutic approaches for the treatment of chronic inflammatory disease.
Timothy D. Mickleborough, Ph.D., FACSM
Human Performance and Exercise Biochemistry Laboratories
Indiana University
References
1. Mickleborough, T. D., M. R. Lindley, A. A. Ionescu, and A. D. Fly. 2006. Protective effect of fish oil supplementation on exercise-induced bronchoconstriction in asthma. Chest 29(1):39-49.
2. Mickleborough, T. D., R. L. Murray, A. A. Ionescu, and M. R. Lindley. 2003. Fish Oil Supplementation Reduces Severity of Exercise- induced Bronchoconstriction in Elite Athletes. Am J Respir Crit Care Med 168(10):1181-9.
3. von Schacky, C., and J. Dyerberg. 2001. omega 3 fatty acids. From eskimos to clinical cardiology--what took us so long? World Rev Nutr Diet 88:90-9.
4. Grimm, H., K. Mayer, P. Mayser, and E. Eigenbrodt. 2002. Regulatory potential of n-3 fatty acids in immunological and inflammatory processes. Br J Nutr 87 Suppl 1:S59-67.
5. Heller, A. R., H. J. Theilen, and T. Koch. 2003. Fish or chips? News Physiol Sci 18:50-4.
6. James, M. J., R. A. Gibson, and L. G. Cleland. 2000. Dietary polyunsaturated fatty acids and inflammatory mediator production. Am J Clin Nutr 71(1 Suppl):343S-8S.
7. Jump, D. B. 2002. The biochemistry of n-3 polyunsaturated fatty acids. J Biol Chem 277(11):8755-8.
8. Mickleborough, T. D., and K. W. Rundell. 2005. Dietary polyunsaturated fatty acids in asthma- and exercise-induced bronchoconstriction. Eur J Clin Nutr 59(12):1335-46.
9. Flower, R. J., and M. Perretti. 2005. Controlling inflammation: a fat chance? J Exp Med 201(5):671-4.
10. Bannenberg, G. L., N. Chiang, A. Ariel, M. Arita, E. Tjonahen, K. H. Gotlinger, S. Hong, and C. N. Serhan. 2005. Molecular circuits of resolution: formation and actions of resolvins and protectins. J Immunol 174(7):4345-55.
11. Arita, M., F. Bianchini, J. Aliberti, A. Sher, N. Chiang, S. Hong, R. Yang, N. A. Petasis, and C. N. Serhan. 2005. Stereochemical assignment, antiinflammatory properties, and receptor for the omega-3 lipid mediator resolvin E1. J Exp Med 201(5):713-22.
12. Li, H., X. Z. Ruan, S. H. Powis, R. Fernando, W. Y. Mon, D. C. Wheeler, J. F. Moorhead, and Z. Varghese. 2005. EPA and DHA reduce LPS- induced inflammation responses in HK-2 cells: evidence for a PPAR-gamma- dependent mechanism. Kidney Int 67(3):867-74.