The Journal of Clinical Investigation COMMENTARY Leukotrienes and sex: strange bedfellows?
Lewis J. Smith Department of Medicine, Northwestern University, Chicago, Illinois, USA.
ed leukotriene levels and the response of these conditions to antileukotriene Leukotrienes are proinflammatory lipid mediators that have been drugs. Several of these diseases have a shown to be upregulated in several diseases, including asthma, aspirin- female predominance and have been exacerbated respiratory disease (AERD), inflammatory bowel disease, associated with sex hormone levels (e.g., and acute respiratory distress syndrome. Leukotrienes have been asthma in adults, AERD) (8, 10). Based on explored as therapeutic targets for these diseases and others; however, these data, it is possible that leukotriene leukotriene inhibitors have had limited success in the clinic. There are modifiers would have a greater effect in noted differences in the incidence of leukotriene-mediated diseases in those with the highest leukotriene levels. males and females, but sex as a factor in the response to leukotriene In this issue, Pace and colleagues build inhibitors has not been fully explored. In this issue of the JCI, Pace and on their previous work and address a colleagues present evidence that there are sex-specific differences in the potential mechanism that may be respon- effectiveness of certain leukotriene inhibitors and link the differences in sible for the relatively limited response to response to the presence of androgens. The results of this study indicate leukotriene modifiers in several disease that sex needs to be taken into consideration in the future evaluation of states (11). Pace et al. exposed male and leukotriene inhibitors to treat disease. female mice and rats as well as peripheral blood cells from male and female human volunteers to inflammatory stimuli and administered different leukotriene syn- Leukotrienes and disease patients with disease. Specifically, leuko thesis inhibitors. The results from this Leukotrienes are bioactive mediators triene expression has been associated with study confirmed their previous findings that were initially identified in the 1970s, asthma (2, 3), aspirin-exacerbated respi- that there are sex-dependent differenc- and the biosynthetic pathways involved ratory disease (AERD) (4), allergic rhini- es in leukotriene biosynthesis and the in leukotriene formation were elucidated tis (5), inflammatory bowel disease (6), effects of leukotriene modifiers and that around the same time (1). The major leu- and acute respiratory distress syndrome these differences are mediated at least kotrienes were designated as leukotriene (7). However, with rare exceptions, such in part by androgens (12). Pace and col-
B4 (LTB4) and as the cysteinyl leukotrienes as AERD (8), leukotriene modifiers have leagues also note that females are more
(LTC 4, LTD4, and LTE4). Subsequent- shown only a modest beneficial effect on likely than males to have 5-LO/FLAP
ly, several leukotriene receptors (BLT1, diseases in which leukotrienes would be complex assembly at the nuclear mem-
BLT 2, CysLT1, CysLT2) were discovered, expected to play an important role. Sever- brane, the site where this complex medi- and small molecules were developed that al explanations, including differences in ates its effects. Additionally, androgens inhibited leukotriene synthesis either by leukotriene levels in individual patients, inhibited the tight assembly, and drugs targeting 5-lipoxygenase (5-LO), 5-LO– the heterogeneity of disease phenotypes, that directly interfered with FLAP and activating protein (FLAP), cytosolic phos- and differences in drug pharmacokinet- 5-LO/FLAP assembly were most likely
pholipase A2 (cPLA2), or molecules, such ics, pharmacodynamics, and pharma- to result in a sex-specific effect. One area as leukotriene receptor antagonists, that cogenomics, have been proposed for why that Pace and colleagues did not explore interfere with the ability of leukotrienes targeting leukotrienes does not benefit is how androgens may alter the inter- to mediate their effects. Increased leukot- leukotriene-related diseases (9); howev- action between 5-LO and FLAP. None- riene production has been linked to sever- er, there has not been a clear explanation theless, their experiments highlight the al inflammatory diseases through a series for why antileukotriene drugs have not complexity of trying to understand the of animal, in vitro, and human studies in worked as expected. role of sex in the differences in leukot- which leukotriene levels were measured riene synthesis and response to leukot- under basal and stimulated conditions and Sex and the response to riene-targeting drugs, as the results were in which the newly developed leukotriene leukotriene inhibition influenced by the specific stimulus and modifiers were administered to various One possible explanation comes from the model system, the type of inflammatory animal species, healthy individuals, and study of diseases associated with elevat- cell (human peripheral blood neutrophils and monocytes and mouse and rat perito- Related Article: p. 3167 neal macrophages), and the leukotriene modifier selected. Even the use of struc- Conflict of interest: The author has declared that no conflict of interest exists. turally dissimilar 5-LO inhibitors showed Reference information: J Clin Invest. 2017;127(8):2895–2896. https://doi.org/10.1172/JCI95717. different effects.
jci.org Volume 127 Number 8 August 2017 2895 COMMENTARY The Journal of Clinical Investigation
Conclusions and future ma, may also provide further informa- 1994;150(3):618–623. directions tion on the role of sex and the response to 4. Szczeklik A, et al. Bronchial aspirin challenge causes specific eicosanoid response in aspirin- This report by Pace and colleagues pro- leukotriene modification. These studies, sensitive asthmatics. Am J Respir Crit Care Med. vides new insights into the influence of sex which enrolled males and females, were 1996;154(6 Pt 1):1608–1614. (and sex hormones) on leukotriene syn- of sufficient size to identify sex-specif- 5. Peters-Golden M, Gleason MM, Togias A. thesis and its inhibition. While the poten- ic differences. It is a bit surprising that a Cysteinyl leukotrienes: multi-functional tial of these results to be of clinical rele- sex-dependent effect on response was not mediators in allergic rhinitis. Clin Exp Allergy. 2006;36(6):689–703. vance is exciting, additional preclinical noted, considering the extensive post hoc 6. Rask-Madsen J, Bukhave K, Laursen LS, Lau- and clinical studies are needed to define analyses that are typically performed on ritsen K. 5-Lipoxygenase inhibitors for the the true clinical impact, which is likely to such clinical trials. It is possible that ear- treatment of inflammatory bowel disease. Agents be complex. For example, Pace et al. focus lier studies of leukotriene modifiers used Actions. 1992;Spec No:C37–C46. primarily on inflammatory processes and doses that did not fully inhibit leukotriene 7. Masclans JR, et al. Possible prognostic value of leukotriene B(4) in acute respiratory distress leukocytes that predominantly generate synthesis. There is a recent interest in using syndrome. Respir Care. 2007;52(12):1695–1700. LTB 4. Although a number of inflammatory higher doses of leukotriene modifiers and 8. Dahlén SE, et al. Improvement of aspirin- diseases, including scleroderma lung dis- in delivering these inhibitors directly to the intolerant asthma by montelukast, a leukotriene ease (13), inflammatory bowel disease (6), organ of interest so that high local concen- antagonist: a randomized, double-blind, placebo- sickle cell disease (14), and cardiovascular trations are achieved. These approaches controlled trial. Am J Respir Crit Care Med. 2002;165(1):9–14. disease (15), are reported to be associated have the potential to be taken advantage 9. Drazen JM, et al. Pharmacogenetic association with increased LTB4 levels, there are few, of for possible identification of sex-depen- between ALOX5 promoter genotype and the if any, examples in which treatment of dent effects that have not previously been response to anti-asthma treatment. Nat Genet. these diseases with leukotriene synthesis seen. For any new study, the influence of 1999;22(2):168–170. inhibitors has shown benefit. The diseas- sex should be a predefined variable and the 10. Postma DS. Gender differences in asthma development and progression. Gend Med. es in which there is the most information statistical analysis powered to identify such 2007;4(Suppl B):S133–S146. relevant to leukotriene biology are asth- an effect. If the clinical studies identify a 11. Pace S, et al. Androgen-mediated sex bias ma, AERD, and allergic rhinitis, to which sex-specific effect on leukotriene synthesis impairs efficiency of leukotriene biosyn- cysteinyl leukotrienes are known to con- inhibitors, it would validate the results of thesis inhibitors in males. J Clin Invest. tribute. For example, well-characterized Pace and colleagues, expand the number of 2017;127(8):3167–3176. 12. Pergola C, et al. ERK-mediated regulation mouse models of asthma have been used drugs whose effects are influenced by sex of leukotriene biosynthesis by androgens: a to study the role of leukotrienes and leu- (18), and possibly lead to sex-specific ther- molecular basis for gender differences in inflam- kotriene modifiers, including cysteinyl apy of a disease that affects large numbers mation and asthma. Proc Natl Acad Sci U S A. leukotriene receptor blockers, which have of men and women. 2008;105(50):19881–19886. become widely used in clinical practice 13. Kowal-Bielecka O, et al. Elevated levels of leuko triene B4 and leukotriene E4 in bronchoalveolar (16, 17). Experiments with disease mod- Acknowledgments lavage fluid from patients with scleroderma lung els that have a demonstrated response to I thank Peter Sporn for his thoughtful disease. Arthritis Rheum. 2003;48(6):1639–1646. leukotriene modification could be used to review and comments. 14. Jennings JE, et al. Elevated urinary leukotriene further explore sex-dependent differences E4 levels are associated with hospitalization for in cysteinyl leukotriene synthesis and the Address correspondence to: Lewis J. Smith, pain in children with sickle cell disease. Am J Hematol. 2008;83(8):640–643. response to leukotriene synthesis inhibi- Northwestern University Feinberg School 15. Hoxha M, Rovati GE, Cavanillas AB. The leukot- tors and receptor blockers. Additionally, of Medicine, 750 N. Lake Shore Drive, riene receptor antagonist montelukast its pos- sufficient numbers of human peripheral Suite 707, Chicago, Illinois 60611, USA. sible role in the cardiovascular field. Eur J Clin blood eosinophils could be obtained from Phone: 312.503.0501; Email: ljsmith@ Pharmacol. 2017;73(7):799. individuals with elevated eosinophils northwestern.edu. 16. Miyahara N, et al. Leukotriene B4 release from counts and used to determine whether or mast cells in IgE-mediated airway hyperrespon- 1. Samuelsson B. The discovery of the leukotrienes. siveness and inflammation. Am J Respir Cell Mol not there are sex-specific differences in Am J Respir Crit Care Med. 2000;161(2 Pt 2):S2–S6. Biol. 2009;40(6):672–682. stimulus-generated cysteinyl leukotriene 2. Smith LJ, Patterson R, Kern R, Krell R, Bernstein 17. Eiymo Mwa Mpollo MS, et al. Placenta growth fac- levels in vitro and/or in the ability of leu- P. Effect of inhaled leukotriene D4 on human tor augments airway hyperresponsiveness kotriene modifiers to block these effects. airways. Ann N Y Acad Sci. 1988;524:298–306. via leukotrienes and IL-13. J Clin Invest. Retrospective analyses of databases 3. Spector SL, Smith LJ, Glass M. Effects of 6 weeks 2016;126(2):571–584. of therapy with oral doses of ICI 204,219, a 18. Legato MJ, Johnson PA, Manson JE. Consider- from studies performed in the 1990s, which leukotriene D4 receptor antagonist, in subjects ation of sex differences in medicine to improve tested leukotriene synthesis inhibitors and with bronchial asthma. ACCOLATE Asthma health care and patient outcomes. JAMA. receptor antagonists in patients with asth- Trialists Group. Am J Respir Crit Care Med. 2016;316(18):1865–1866.
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