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Inflammation Resolution: NSAIDs, Eicosanoids, and Steroids [ Medical Education ](https://mdster.com/blog?category=medical-education) Inflammation Resolution: NSAIDs, Eicosanoids, and Steroids ============================================================ A board-focused clinical guide to how prostaglandins, leukotrienes, NSAIDs, and glucocorticoids shape the end of inflammation [ MDster Editorial Team ](https://mdster.com/about) · Jul 21, 2026 · 7 min read · 25 [ Reviewed by Dr. Ali Ragab, MBBCH, MSc, MCAI ](https://mdster.com/medical-reviewers/dr-ali-ragab) [Editorial Policy](https://mdster.com/editorial-policy) | [Corrections Policy](https://mdster.com/corrections) [ Board Review ](https://mdster.com/blog?tag=board-review) [ Internal Medicine ](https://mdster.com/blog?tag=internal-medicine) [ Immunology ](https://mdster.com/blog?tag=immunology) [ Pharmacology ](https://mdster.com/blog?tag=pharmacology) [ Inflammation ](https://mdster.com/blog?tag=inflammation) ![Inflammation Resolution: NSAIDs, Eicosanoids, and Steroids](https://mdster.com/storage/blog/images/inflammation-resolution-nsaids-eicosanoids-and-steroids.jpg) Share this article Share this post On this page 1. [ Resolution is active, not passive ](#resolution-is-active-not-passive) 2. [ What actually has to happen ](#what-actually-has-to-happen) 3. [ The lipid mediator switch: where boards like to test you ](#the-lipid-mediator-switch-where-boards-like-to-test-you) 4. [ How NSAIDs help symptoms and cause predictable harm ](#how-nsaids-help-symptoms-and-cause-predictable-harm) 5. [ Mechanistic links you should know cold ](#mechanistic-links-you-should-know-cold) 6. [ Steroids: broader, more upstream, and more potent ](#steroids-broader-more-upstream-and-more-potent) 7. [ Clinical correlations for Internal Medicine ](#clinical-correlations-for-internal-medicine) 8. [ Key Takeaways ](#key-takeaways) 9. [ Conclusion ](#conclusion) 10. [ Frequently Asked Questions ](#blog-faqs) 11. [ References ](#references-heading) On this page 1. [ Resolution is active, not passive ](#resolution-is-active-not-passive) 2. [ What actually has to happen ](#what-actually-has-to-happen) 3. [ The lipid mediator switch: where boards like to test you ](#the-lipid-mediator-switch-where-boards-like-to-test-you) 4. [ How NSAIDs help symptoms and cause predictable harm ](#how-nsaids-help-symptoms-and-cause-predictable-harm) 5. [ Mechanistic links you should know cold ](#mechanistic-links-you-should-know-cold) 6. [ Steroids: broader, more upstream, and more potent ](#steroids-broader-more-upstream-and-more-potent) 7. [ Clinical correlations for Internal Medicine ](#clinical-correlations-for-internal-medicine) 8. [ Key Takeaways ](#key-takeaways) 9. [ Conclusion ](#conclusion) 10. [ Frequently Asked Questions ](#blog-faqs) 11. [ References ](#references-heading) A gout flare gets treated with ibuprofen, the joint pain improves, and 48 hours later the creatinine is up, the ankles are swollen, and the blood pressure is worse. That is not random bad luck. It is what happens when you interfere with lipid mediators that drive inflammation but also protect kidney, gut, vasculature, and the biology of resolution itself. [\[1\]](#cite-1 "Reference [1]") Resolution is active, not passive --------------------------------- Do not think of resolution as inflammation simply fading away. Acute inflammation resolves through an organized program: neutrophil recruitment stops, existing neutrophils undergo apoptosis, macrophages clear them by efferocytosis, pro-inflammatory signals fall, and tissue repair pathways turn on. Failure of that program is one route to chronic inflammatory disease. [\[2\]](#cite-2 "Reference [2]") ### What actually has to happen The high-yield sequence is straightforward: - Eliminate the trigger. - Stop further neutrophil trafficking. - Clear apoptotic cells by macrophage efferocytosis. - Shift macrophages toward a reparative phenotype and restore tissue homeostasis. [\[2\]](#cite-2 "Reference [2]") > Clinical Pearl: Anti-inflammatory is not automatically pro-resolution. A drug can suppress symptoms early yet still disrupt later stop signals that normally terminate inflammation. [\[3\]](#cite-3 "Reference [3]") The lipid mediator switch: where boards like to test you -------------------------------------------------------- Arachidonic acid sits at the center. COX enzymes generate prostanoids such as **PGE2**, **PGI2**, and thromboxane, while 5-lipoxygenase generates leukotrienes such as **LTB4** and the cysteinyl leukotrienes **LTC4/LTD4/LTE4**. Early inflammation uses these mediators to create vasodilation, permeability, pain, fever, neutrophil recruitment, and in the airways, bronchoconstriction. [\[4\]](#cite-4 "Reference [4]") PathwayDominant mediatorsBedside consequenceCOXPGE2, PGI2, TXA2Pain, fever, vascular tone, platelet effects, mucosal and renal homeostasis5-LOXLTB4, LTC4/LTD4/LTE4Neutrophil chemotaxis, bronchospasm, edema, mucusResolution phaseLipoxins, resolvins, protectins, maresinsStop leukocyte influx, enhance efferocytosis, promote repair Memorize the twist: not all prostaglandins are purely pro-inflammatory. PGE2 and PGD2 help initiate the later class switch toward lipoxins and other specialized pro-resolving mediators, and some downstream prostanoids also participate in turning inflammation off. That is why the exam trap is assuming every prostaglandin is simply bad and every COX blockade is uniformly good. [\[5\]](#cite-5 "Reference [5]") Aspirin is the important exception. Unlike other NSAIDs, acetylated COX-2 can still generate intermediates that are converted to aspirin-triggered lipoxins and resolvins, which is why aspirin is often described as more resolution-friendly than routine COX blockade. [\[6\]](#cite-6 "Reference [6]") How NSAIDs help symptoms and cause predictable harm --------------------------------------------------- NSAIDs work because they reduce prostaglandin synthesis. The adverse effects make sense only if you remember what those prostaglandins were doing for normal physiology. The same pathway that amplifies pain and fever also maintains gastric defense, renal perfusion under stress, vascular homeostasis, and in some patients restrains leukotriene-driven airway disease. [\[7\]](#cite-7 "Reference [7]") ### Mechanistic links you should know cold - **GI toxicity:** loss of mucosal prostaglandins lowers mucus and bicarbonate secretion and reduces mucosal blood flow, making ulceration and bleeding more likely. Misoprostol works precisely because it replaces a prostaglandin signal. [\[7\]](#cite-7 "Reference [7]") - **Renal toxicity:** when kidney perfusion is threatened, renal prostaglandins help maintain afferent vasodilation. Block them and GFR can fall, especially in CKD, heart failure, cirrhosis, dehydration, or with diuretics plus ACE inhibitor or ARB therapy. [\[1\]](#cite-1 "Reference [1]") - **Edema, hypertension, heart failure worsening:** reduced renal prostaglandin activity promotes sodium and water retention. [\[8\]](#cite-8 "Reference [8]") - **Cardiovascular thrombosis risk:** suppressing endothelial **PGI2** while leaving platelet thromboxane relatively unopposed shifts toward thrombosis; this is most classically emphasized with COX-2 selective inhibition, though risk is not confined to coxibs alone. [\[9\]](#cite-9 "Reference [9]") - **AERD:** COX-1 inhibition removes the protective PGE2 brake and favors leukotriene excess, producing bronchospasm, nasal symptoms, and severe type 2 airway inflammation in susceptible patients. [\[10\]](#cite-10 "Reference [10]") Board pitfall: COX-2 selectivity lowers GI toxicity relative to nonselective NSAIDs, but it does **not** eliminate renal risk and does **not** make the drug cardiovascularly neutral. [\[11\]](#cite-11 "Reference [11]") Steroids: broader, more upstream, and more potent ------------------------------------------------- Glucocorticoids act above the eicosanoid level. After binding the glucocorticoid receptor, they repress pro-inflammatory transcription factors such as **NF-kB** and **AP-1**, induce inhibitory proteins such as **GILZ** and **IkB**, reduce **COX-2** expression, and upregulate **annexin A1**, which restrains phospholipase A2 and therefore decreases arachidonic acid release. The net effect is less substrate for both prostaglandins and leukotrienes, plus less cytokine transcription overall. [\[12\]](#cite-12 "Reference [12]") Clinically, that explains why steroids work so fast and so broadly in asthma and COPD exacerbations, gout, autoimmune flares, and vasculitis. But do not confuse power with precision: steroids suppress inflammatory gene programs widely, whereas endogenous resolution is a more targeted choreography of stop signals, efferocytosis, and repair. [\[12\]](#cite-12 "Reference [12]") Clinical correlations for Internal Medicine ------------------------------------------- When you choose an anti-inflammatory drug, ask one question first: what protective prostaglandin function am I about to sacrifice in this patient? In the older patient with CKD and HF on a loop diuretic plus an ACE inhibitor, the answer is renal perfusion and salt-water balance. In the patient with nasal polyps and asthma, the answer may be a leukotriene surge. [\[1\]](#cite-1 "Reference [1]") If NSAIDs are necessary in a patient with substantial ulcer risk, risk-stratify carefully and use gastroprotection when indicated. If steroids are necessary, use them deliberately as the right tool for the right inflammatory phenotype, not as a reflex for every elevated CRP. [\[13\]](#cite-13 "Reference [13]") Key Takeaways ------------- - Resolution of inflammation is an **active** biologic program centered on stopping neutrophil influx, promoting efferocytosis, and restoring tissue homeostasis. [\[2\]](#cite-2 "Reference [2]") - Prostaglandins and leukotrienes start inflammation, but some prostaglandin signals also help trigger the later lipid mediator class switch toward resolution. [\[5\]](#cite-5 "Reference [5]") - NSAID toxicities are mechanistically coherent: GI bleeding, AKI, edema, hypertension, HF worsening, thrombosis risk, and AERD all follow from prostaglandin pathway disruption. [\[7\]](#cite-7 "Reference [7]") - Aspirin is pharmacologically unique because acetylated COX-2 can generate aspirin-triggered pro-resolving mediators. [\[6\]](#cite-6 "Reference [6]") - Steroids act upstream by suppressing inflammatory transcription and reducing arachidonic acid availability through annexin A1 and related pathways. [\[12\]](#cite-12 "Reference [12]") Conclusion ---------- If you remember only one mental model, remember this: inflammation resolution is not the absence of inflammation but the presence of organized stop signals. Good internists do not just ask how to block inflammation. They ask how their treatment changes the biology of getting the patient back to homeostasis. [\[2\]](#cite-2 "Reference [2]") Frequently Asked Questions ---------------------------- ### Why can an NSAID raise creatinine so quickly in a hospitalized patient? Because renal prostaglandins help preserve prostaglandin-dependent kidney blood flow during physiologic stress. COX inhibition removes that buffer, so GFR can fall quickly, especially with CKD, HF, cirrhosis, dehydration, or concurrent diuretics plus ACE inhibitor or ARB therapy. [\[1\]](#cite-1 "Reference [1]") ### Are prostaglandins always pro-inflammatory? No. Many prostaglandins amplify pain, fever, and vascular changes early, but some prostaglandin signals also help initiate the later lipid mediator class switch toward lipoxins and other pro-resolving mediators. [\[5\]](#cite-5 "Reference [5]") ### Why can aspirin be pro-resolving in one context and trigger respiratory reactions in another? Aspirin can acetylate COX-2 and generate aspirin-triggered lipoxins or resolvins, but in patients with AERD, COX-1 inhibition can still drive cysteinyl leukotriene excess and bronchospasm. Context and host phenotype matter. [\[6\]](#cite-6 "Reference [6]") ### How do steroids reduce both prostaglandins and leukotrienes? They act upstream of both pathways. Glucocorticoids induce annexin A1, which restrains phospholipase A2 and decreases arachidonic acid release, while also repressing inflammatory transcription factors and reducing COX-2 expression. [\[12\]](#cite-12 "Reference [12]") References (15) ------------------- 1. 1. [ KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease ](https://kdigo.org/wp-content/uploads/2024/03/KDIGO-2024-CKD-Guideline.pdf?_kx=7mpq_HsU2qGtCXwsHcEfvUCiDeCHI1JA9j2U8-Nmr9IP-ESLznUGilIvllIUVP1J.SEZpxg) [↩](#cite-ref-1-1 "Back to text") 2. 2. [ pmc.ncbi.nlm.nih.gov/articles/PMC4004957 ](https://pmc.ncbi.nlm.nih.gov/articles/PMC4004957/) [↩](#cite-ref-2-1 "Back to text") 3. 3. [ Resolution of Inflammation: What Controls Its Onset? ](https://pmc.ncbi.nlm.nih.gov/articles/PMC4845539/) [↩](#cite-ref-3-1 "Back to text") 4. 4. [ pmc.ncbi.nlm.nih.gov/articles/PMC8312722 ](https://pmc.ncbi.nlm.nih.gov/articles/PMC8312722/) [↩](#cite-ref-4-1 "Back to text") 5. 5. [ Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators ](https://pmc.ncbi.nlm.nih.gov/articles/PMC2744593/) [↩](#cite-ref-5-1 "Back to text") 6. 6. [ pmc.ncbi.nlm.nih.gov/articles/PMC4295924 ](https://pmc.ncbi.nlm.nih.gov/articles/PMC4295924/) [↩](#cite-ref-6-1 "Back to text") 7. 7. [ www.accessdata.fda.gov/drugsatfda\_docs/nda/2002/076095.pdf ](https://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/076095.pdf) [↩](#cite-ref-7-1 "Back to text") 8. 8. [ pmc.ncbi.nlm.nih.gov/articles/PMC7422842 ](https://pmc.ncbi.nlm.nih.gov/articles/PMC7422842/) [↩](#cite-ref-8-1 "Back to text") 9. 9. [ pmc.ncbi.nlm.nih.gov/articles/PMC5676556 ](https://pmc.ncbi.nlm.nih.gov/articles/PMC5676556/) [↩](#cite-ref-9-1 "Back to text") 10. 10. [ pubmed.ncbi.nlm.nih.gov/36184313 ](https://pubmed.ncbi.nlm.nih.gov/36184313/) [↩](#cite-ref-10-1 "Back to text") 11. 11. [ pmc.ncbi.nlm.nih.gov/articles/PMC10591119 ](https://pmc.ncbi.nlm.nih.gov/articles/PMC10591119/) [↩](#cite-ref-11-1 "Back to text") 12. 12. [ Immune regulation by glucocorticoids ](https://pmc.ncbi.nlm.nih.gov/articles/PMC9761406/) [↩](#cite-ref-12-1 "Back to text") 13. 13. [ pubmed.ncbi.nlm.nih.gov/28257716 ](https://pubmed.ncbi.nlm.nih.gov/28257716/) [↩](#cite-ref-13-1 "Back to text") 14. 14. [ CELEBREX (celecoxib) capsules, for oral use: Prescribing Information ](https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/020998s056lbl.pdf) 15. 15. [ Nonsteroidal Anti-Inflammatory Drug-Induced Peptic Ulcer Disease ](https://pmc.ncbi.nlm.nih.gov/articles/PMC12173566/) Study pathway Turn reading into Internal Medicine performance ------------------------------------------------- - System‑based, exam‑style questions + explanations - Smarter review to reinforce weak topics - Build confidence with measurable progress Free 5-day trial No credit card required. 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