https://orcid.org/0000-0002-9768-0262
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Marc Peters-Golden, The Chemical Elucidation of Slow-Reacting Substance: Bronchospasm and Beyond, The Journal of Immunology, Volume 200, Issue 5, March 2018, Pages 1535–1537, https://doi.org/10.4049/jimmunol.1800037
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In 1860, H.H. Salter first noted the importance of bronchial smooth muscle contraction in asthma (1). Eighty years later, Kellaway et al. (2) recognized a distinctive bioactivity whose release following Ag challenge of sensitized lung elicited a contractile response that was slower in onset and more protracted than that elicited by histamine, the only known spasmogen of the time; they named this material “slow-reacting substance” (SRS). In 1960, W. Brocklehurst recognized that whereas histamine existed preformed, SRS was instead generated de novo during the Ag–Ab reaction, suggesting an enzymatic mechanism (3). These foundational observations sparked the quest to elucidate the chemical structure of SRS and its mechanism of biosynthesis—a quest that would ultimately require two more decades.
Although research by a number of laboratories around the world had provided certain methodologic and compositional clues to the identity of SRS, the data were ambiguous and progress was limited by the small quantities of biological material available for analysis. During the 1960s and 1970s, Samuelsson et al. (4) at the Karolinska Institute had accumulated substantial expertise in lipid structural analysis and the biochemistry of arachidonic acid oxygenation via cyclooxygenase and lipoxygenase pathways (5). This expertise would prove instrumental in solving the SRS puzzle, as described in the featured 1979 Pillars of Immunology article (6). R.C. Murphy, a visiting scientist working with the Samuelsson group, used calcium ionophore–stimulated mouse mastocytoma cells to generate sufficient quantities of spasmogenic SRS for analysis. This material incorporated isotopically labeled arachidonic acid and cysteine, and had four double bonds. Its UV absorption spectrum was consistent with that of a conjugated triene chromophore. As SRS was formed by leukocytes, they coined the term “leukotriene” (LT) and designated this structure LTC4. The cysteine-containing moiety was eventually determined to be the tripeptide glutathione, and SRS was subsequently revealed to represent a mixture of LTC4 plus two bioactive degradation products, LTD4 and LTE4, formed from the sequential removal of glutamic acid and glycine, respectively. As all three family members contained cysteine, these were collectively called cysteinyl LTs (cysLTs) (7). For this and other foundational work, Samuelsson was awarded the 1982 Nobel Prize for Physiology or Medicine.
