{"id":"259b8eb3-90ac-5cf2-b29b-0eba9a282d4d","stable_key":"f8641d02-8413-5bd8-92e9-62ad49286e81:asa-shunting-does-not-track","predicate":"preserves_measured_pool","statement":"Excretion of leukotriene E4 was increased by a mean of 361% during aspirin-induced asthma episodes, but the degree of increase for individual patients did not correlate with the degree of bronchospasm or with inhibition of platelet thromboxane B2 formation, so although endogenous synthesis of potent bronchoconstrictor leukotrienes increases during aspirin-induced bronchospasm it appears unlikely that direct shunting of unmetabolised arachidonate into leukotriene synthesis represents the mechanism of aspirin-induced asthma.","claim_class":"observational","status":"source_derived_draft","evidence_grade":"ungraded","direction":"neutral","is_public":true,"mechanism_event_id":"a299f04b-5c88-5050-beff-ce182f7ed20a","mechanism_event_label":"The leukotrienes do rise, but how much they rise says nothing about how badly the patient wheezes.","subject":{"id":"77ae6efc-6185-5263-a439-07411e3a881d","slug":"leukotriene-e4-excretion","display_name":"Urinary leukotriene E4 excretion","entity_type_key":"cellular_process"},"object":{"id":"39334ff3-8348-5104-892c-418806fedde7","slug":"bronchospasm","display_name":"Aspirin-induced bronchospasm","entity_type_key":"cellular_process"},"evidence_count":1,"mechanism_event":{"id":"a299f04b-5c88-5050-beff-ce182f7ed20a","stable_key":"f8641d02-8413-5bd8-92e9-62ad49286e81:asa-shunting-does-not-track-event","event_type":"observed_intervention","label":"The leukotrienes do rise, but how much they rise says nothing about how badly the patient wheezes.","description":"Excretion of leukotriene E4 was increased by a mean of 361% during aspirin-induced asthma episodes, but the degree of increase for individual patients did not correlate with the degree of bronchospasm or with inhibition of platelet thromboxane B2 formation, so although endogenous synthesis of potent bronchoconstrictor leukotrienes increases during aspirin-induced bronchospasm it appears unlikely that direct shunting of unmetabolised arachidonate into leukotriene synthesis represents the mechanism of aspirin-induced asthma.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"48bd3537-336a-512d-be9e-69faf8a45b1a","slug":"arachidonate-shunting","display_name":"Diversion of unmetabolised arachidonate into the 5-lipoxygenase pathway","entity_type_key":"cellular_process"},"role":"tested_hypothesis","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"7f2ceef8-279f-5e28-9341-ba8edeb7cc38","slug":"aspirin-exacerbated-respiratory-disease","display_name":"Aspirin-sensitive asthma and rhinitis","entity_type_key":"cellular_process"},"role":"studied_condition","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"c5e111fb-13e9-53ab-8931-9b553fa5a263","slug":"serum-thromboxane-b2","display_name":"Serum thromboxane B2 after whole blood clotting","entity_type_key":"cellular_process"},"role":"co_measured","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""},{"entity":{"id":"77ae6efc-6185-5263-a439-07411e3a881d","slug":"leukotriene-e4-excretion","display_name":"Urinary leukotriene E4 excretion","entity_type_key":"cellular_process"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":3,"notes":""},{"entity":{"id":"39334ff3-8348-5104-892c-418806fedde7","slug":"bronchospasm","display_name":"Aspirin-induced bronchospasm","entity_type_key":"cellular_process"},"role":"target","stoichiometry":null,"state_label":"","sequence_order":4,"notes":""}]},"contexts":[{"dimension":"evidence_span","value_text":"{\"source_cache\": \"artifacts/aspirin-research/1309376.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"115a13f9e08205c2b6ea376e5a1fcb90cc6887b277041acc114908c7d85f6e05\", \"start_char\": 0, \"end_char\": 1427, \"text_sha256\": \"115a13f9e08205c2b6ea376e5a1fcb90cc6887b277041acc114908c7d85f6e05\"}","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Urinary leukotriene E4 measured during aspirin-induced asthma episodes across a range of provoking doses","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"exposure","value_text":"Aspirin doses from 30 to 365 milligrams in individual aspirin-sensitive patients","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"Tests the shunting hypothesis by asking whether the leukotriene rise tracks the bronchospasm, which it does not. Urinary leukotriene E4 is a whole-body measure rather than an airway one.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"nutrient_topic","value_text":"Aspirin research collection; topical membership is not evidence of a direct clinical effect, and aspirin is recorded separately from salicylate, the metabolite it becomes.","comparator":null,"unit":null,"notes":"","entity":{"slug":"aspirin","display_name":"Aspirin / acetylsalicylic acid","entity_type_key":"drug"}},{"dimension":"organism","value_text":"Human","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"plain_language","value_text":"The leukotrienes do rise, but how much they rise says nothing about how badly the patient wheezes.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"[asa-p1309376] Increased excretion of leukotriene E4 during aspirin-induced asthma. (1992). https://pubmed.ncbi.nlm.nih.gov/1309376/","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"tissue_or_cell_type","value_text":"Airway and urine","comparator":null,"unit":null,"notes":"","entity":null}],"evidence":[{"id":"27191644-b234-5e1b-991f-af12daa7740a","evidence_kind":"source_excerpt","locator":"Lines 559-570","start_line":559,"end_line":570,"excerpt":"### asa-shunting-does-not-track\nExcretion of leukotriene E4 was increased by a mean of 361% during aspirin-induced asthma episodes, but the degree of increase for individual patients did not correlate with the degree of bronchospasm or with inhibition of platelet thromboxane B2 formation, so although endogenous synthesis of potent bronchoconstrictor leukotrienes increases during aspirin-induced bronchospasm it appears unlikely that direct shunting of unmetabolised arachidonate into leukotriene synthesis represents the mechanism of aspirin-induced asthma.\nCondition category: normal\nnutrient_topic: Aspirin research collection; topical membership is not evidence of a direct clinical effect, and aspirin is recorded separately from salicylate, the metabolite it becomes.\nplain_language: The leukotrienes do rise, but how much they rise says nothing about how badly the patient wheezes.\norganism: Human\ntissue_or_cell_type: Airway and urine\nexperimental_model: Urinary leukotriene E4 measured during aspirin-induced asthma episodes across a range of provoking doses\nlimitations: Tests the shunting hypothesis by asking whether the leukotriene rise tracks the bronchospasm, which it does not. Urinary leukotriene E4 is a whole-body measure rather than an airway one.\nexposure: Aspirin doses from 30 to 365 milligrams in individual aspirin-sensitive patients\nevidence_span: {\"source_cache\": \"artifacts/aspirin-research/1309376.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"115a13f9e08205c2b6ea376e5a1fcb90cc6887b277041acc114908c7d85f6e05\", \"start_char\": 0, \"end_char\": 1427, \"text_sha256\": \"115a13f9e08205c2b6ea376e5a1fcb90cc6887b277041acc114908c7d85f6e05\"}\n[asa-p1309376] Increased excretion of leukotriene E4 during aspirin-induced asthma. (1992). https://pubmed.ncbi.nlm.nih.gov/1309376/","model_system":"Urinary leukotriene E4 measured during aspirin-induced asthma episodes across a range of provoking doses","directness":"author_interpretation","verification_status":"source_derived_draft","notes":"Exact curation-document quotation, not publisher quotation. Study references: [asa-p1309376] Increased excretion of leukotriene E4 during aspirin-induced asthma. (1992). https://pubmed.ncbi.nlm.nih.gov/1309376/","relationship":"supports","weight":1.0,"link_notes":"","source":{"id":"712cf519-cd27-5a8b-9e2f-961a98d7a27e","stable_key":"import-f8641d02-8413-5bd8-92e9-62ad49286e81","title":"Aspirin: the serine it acetylates, the enzyme that acetylation creates, the dose that separates platelet from vessel wall, and the metabolite that is a different drug (2026-09-22)","document_type":"imported_text","citation_label":"AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text.","file_path":"","sha256":"93dd4343051c131e40d4fc3c95a978cd65478c13dcdb3f2d42507c49b09cb647","revision_id":"694e8ee7-49ca-5e6c-b58b-8ba8f82c2ad8","review_status":"unverified_draft","notes":""}}],"relations":[],"conflicts":[{"id":"401adcee-a588-55e2-9b19-57893d80a1e8","title":"Is aspirin-induced asthma caused by arachidonate spilling into the leukotriene pathway?","kind":"contradiction","status":"open","why":"The long-standing proposal is that inhibiting cyclooxygenase removes a protective prostaglandin brake and diverts unmetabolised arachidonate into the 5-lipoxygenase pathway, producing bronchoconstrictor leukotrienes. Measuring urinary leukotriene E4 during provoked episodes across doses from 30 to 365 milligrams confirmed a mean 361% rise but found that the size of the rise in an individual predicted neither the severity of bronchospasm nor the degree of cyclooxygenase inhibition, and those authors concluded direct shunting is unlikely to be the mechanism. A nasal challenge study found peptide leukotrienes released only in sensitive patients and not in insensitive patients or healthy subjects, which locates the abnormality in the patient rather than in the amount of substrate diverted. Separately, an enzyme study in this collection notes that aspirin-acetylated cyclooxygenase-2 keeps metabolising arachidonate efficiently and so does not cause it to accumulate. The leukotrienes are real and the dose-dependence on cyclooxygenase potency is real; the simple shunting account of why is not supported.","resolution":"Unresolved; needs review.","created_at":"2026-09-22 06:15:08","record_type":"conflict","display_label":"Recorded conflict","record_url":"/conflicts/401adcee-a588-55e2-9b19-57893d80a1e8","sides":[{"conflict_id":"401adcee-a588-55e2-9b19-57893d80a1e8","ordinal":0,"label":"The standard explanation: block one pathway and the raw material spills into another that makes bronchoconstrictors.","revision_id":"694e8ee7-49ca-5e6c-b58b-8ba8f82c2ad8","start_line":546,"end_line":557,"quote":"### asa-shunting-proposed\nThe adverse effect of aspirin in asthmatics is often attributed to inhibition of the synthesis and release of defensive modulatory endogenous prostaglandins in the lungs, removing their negative feedback on allergic mediator release, and in addition work suggests diversion of arachidonic acid metabolism via the lipoxygenase pathway after cyclooxygenase inhibition, leading to formation of hydroperoxy acids and leukotrienes whose accumulation in sensitive individuals could explain the mechanism of aspirin-induced asthma.\nCondition category: normal\nnutrient_topic: Aspirin research collection; topical membership is not evidence of a direct clinical effect, and aspirin is recorded separately from salicylate, the metabolite it becomes.\nplain_language: The standard explanation: block one pathway and the raw material spills into another that makes bronchoconstrictors.\norganism: Human\ntissue_or_cell_type: Airway\nexperimental_model: Review of arachidonate metabolism in airway hyperreactivity and aspirin-induced asthma\nlimitations: A review from 1981 setting out the shunting hypothesis. It is recorded as the proposal that later work tested, not as evidence that the proposal is right.\nexposure: Cyclooxygenase inhibition and the proposed diversion of arachidonate into the lipoxygenase pathway\nevidence_span: {\"source_cache\": \"artifacts/aspirin-research/6113615.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"184fc232146a3837f396109d951c9755155f181c524a3ffaa330645138d8a616\", \"start_char\": 0, \"end_char\": 2083, \"text_sha256\": \"184fc232146a3837f396109d951c9755155f181c524a3ffaa330645138d8a616\"}\n[asa-p6113615] Lipoxygenase pathway and hydroperoxy acids: possible relevance to aspirin-induced asthma and hyperirritability of airways in asthmatics. (1981). https://pubmed.ncbi.nlm.nih.gov/6113615/ DOI: 10.1016/0161-4630(81)90097-5","source_key":"import-f8641d02-8413-5bd8-92e9-62ad49286e81","source_title":"Aspirin: the serine it acetylates, the enzyme that acetylation creates, the dose that separates platelet from vessel wall, and the metabolite that is a different drug (2026-09-22)","claim_ids":["ed7234ce-9d92-5ede-b29d-19e16f475a5f"]},{"conflict_id":"401adcee-a588-55e2-9b19-57893d80a1e8","ordinal":1,"label":"The leukotrienes do rise, but how much they rise says nothing about how badly the patient wheezes.","revision_id":"694e8ee7-49ca-5e6c-b58b-8ba8f82c2ad8","start_line":559,"end_line":570,"quote":"### asa-shunting-does-not-track\nExcretion of leukotriene E4 was increased by a mean of 361% during aspirin-induced asthma episodes, but the degree of increase for individual patients did not correlate with the degree of bronchospasm or with inhibition of platelet thromboxane B2 formation, so although endogenous synthesis of potent bronchoconstrictor leukotrienes increases during aspirin-induced bronchospasm it appears unlikely that direct shunting of unmetabolised arachidonate into leukotriene synthesis represents the mechanism of aspirin-induced asthma.\nCondition category: normal\nnutrient_topic: Aspirin research collection; topical membership is not evidence of a direct clinical effect, and aspirin is recorded separately from salicylate, the metabolite it becomes.\nplain_language: The leukotrienes do rise, but how much they rise says nothing about how badly the patient wheezes.\norganism: Human\ntissue_or_cell_type: Airway and urine\nexperimental_model: Urinary leukotriene E4 measured during aspirin-induced asthma episodes across a range of provoking doses\nlimitations: Tests the shunting hypothesis by asking whether the leukotriene rise tracks the bronchospasm, which it does not. Urinary leukotriene E4 is a whole-body measure rather than an airway one.\nexposure: Aspirin doses from 30 to 365 milligrams in individual aspirin-sensitive patients\nevidence_span: {\"source_cache\": \"artifacts/aspirin-research/1309376.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"115a13f9e08205c2b6ea376e5a1fcb90cc6887b277041acc114908c7d85f6e05\", \"start_char\": 0, \"end_char\": 1427, \"text_sha256\": \"115a13f9e08205c2b6ea376e5a1fcb90cc6887b277041acc114908c7d85f6e05\"}\n[asa-p1309376] Increased excretion of leukotriene E4 during aspirin-induced asthma. (1992). https://pubmed.ncbi.nlm.nih.gov/1309376/","source_key":"import-f8641d02-8413-5bd8-92e9-62ad49286e81","source_title":"Aspirin: the serine it acetylates, the enzyme that acetylation creates, the dose that separates platelet from vessel wall, and the metabolite that is a different drug (2026-09-22)","claim_ids":["259b8eb3-90ac-5cf2-b29b-0eba9a282d4d"]}]}],"corrections":[],"research":null}