What Are Leukotrienes and How Do They Affect Health?

Leukotrienes are a family of signaling molecules your body makes from fatty acids, and their primary job is to drive inflammation. They were first detected in 1938 as a mysterious substance that made smooth muscle contract, known for decades only as “slow reacting substance of anaphylaxis” before their chemical structure was finally identified in 1979 and the name “leukotriene” was coined.¹ Today they are recognized as potent mediators of asthma, allergies, and a growing list of inflammatory conditions across multiple organ systems. Understanding what they do, and what happens when they go into overdrive, helps explain everything from why your airways tighten during a workout to why certain medications carry psychiatric side-effect warnings.

How Your Body Produces Leukotrienes

Leukotrienes start as arachidonic acid, a type of omega-6 fatty acid embedded in your cell membranes. When immune cells sense injury, infection, or an allergen, they release arachidonic acid and hand it off to an enzyme called 5-lipoxygenase. That enzyme, with help from a partner protein called FLAP (5-lipoxygenase activating protein), converts arachidonic acid through a couple of chemical steps into a precursor molecule called leukotriene A4.² From there, the pathway forks into two branches that produce two distinct types of leukotrienes, each with different biological effects.

The Two Families and What They Do

Leukotriene A4 is unstable and gets quickly converted into one of two product families. One branch produces leukotriene B4 (LTB4), which acts mainly as a chemical beacon for white blood cells, pulling neutrophils toward sites of inflammation. The other branch produces the cysteinyl leukotrienes (LTC4, LTD4, and LTE4), which are the molecules most associated with the tightening of airways, swelling of tissues, and ramped-up mucus production in allergic and respiratory diseases.

LTB4 works through a receptor called BLT1, which sits on the surface of neutrophils. Research using animal models of inflammatory arthritis found that BLT1 on neutrophils was absolutely required for those immune cells to flood into inflamed joints and sustain the inflammatory cycle.³ What made this finding striking was that BLT1-expressing neutrophils did not just show up themselves; they also recruited additional neutrophils that lacked the receptor, essentially amplifying the inflammatory signal far beyond the initial wave. The same LTB4-BLT1 pathway has been implicated in kidney damage during certain drug toxicities, where neutrophil recruitment to the kidneys drives tissue injury.⁴

Cysteinyl leukotrienes, by contrast, exert their effects through a different pair of receptors called CysLT1 and CysLT2. CysLT1 is the main target of common asthma medications. CysLT2 appears to play a broader role in vascular biology: when researchers engineered mice to overexpress CysLT2 on blood vessel cells, those animals showed increased vascular permeability, altered blood pressure responses, and heightened anaphylactic reactions in the skin.⁵ This vascular dimension of leukotriene signaling is one reason researchers now look at these molecules well beyond the lungs.

Leukotrienes in Asthma and Exercise-Induced Breathing Difficulty

The connection between cysteinyl leukotrienes and asthma is one of the most thoroughly studied areas in leukotriene biology. These molecules promote bronchoconstriction (the tightening of airway smooth muscle), increase mucus secretion, and attract immune cells to the airway lining, all of which make breathing harder.⁶ People with asthma who also have exercise-induced bronchoconstriction tend to have elevated levels of cysteinyl leukotrienes in their airways, and exercise itself can trigger a sustained spike in these molecules.⁷

What makes exercise-induced bronchoconstriction particularly interesting is that cysteinyl leukotrienes from the airway lining cells themselves, not just from infiltrating immune cells, appear to drive the problem. A mouse study found that repeated strenuous exercise led to both airway hyperresponsiveness and structural remodeling of the airways, and treatment with montelukast (a drug that blocks the CysLT1 receptor) significantly reduced both outcomes.⁸ That result underscores why leukotriene-blocking drugs are a first-line option for people whose asthma flares during physical activity.

There is also evidence that measuring cysteinyl leukotriene levels in exhaled breath or sputum can serve as a marker of asthma severity and airway inflammation, giving clinicians a noninvasive way to gauge how active the disease is.⁹

Aspirin-Exacerbated Respiratory Disease

One condition where leukotrienes take center stage is aspirin-exacerbated respiratory disease, or AERD, sometimes called Samter’s triad. People with AERD develop severe asthma symptoms, nasal polyps, and respiratory reactions when they take aspirin or other nonsteroidal anti-inflammatory drugs. The underlying problem involves a fundamental imbalance: the body underproduces anti-inflammatory prostaglandins (specifically prostaglandin E2) while overproducing cysteinyl leukotrienes.¹⁰ When aspirin shuts down the cyclooxygenase pathway (the one that makes prostaglandins), whatever brake prostaglandin E2 was applying to leukotriene production gets released, and cysteinyl leukotriene levels surge.

This is a good example of how leukotrienes do not operate in isolation. Inflammation is governed by a tug-of-war between pro-inflammatory and anti-inflammatory lipid signals, and AERD represents a case where that balance is already tilted before the patient swallows an aspirin. Leukotriene receptor antagonists are commonly prescribed to people with AERD as part of their daily management, and the condition is often flagged through elevated urinary leukotriene E4 levels.

Nasal Polyps and Upper Airway Inflammation

Chronic rhinosinusitis with nasal polyps is another condition where leukotrienes play a meaningful role, and one that is often frustratingly resistant to standard treatments. A systematic review found that leukotriene antagonists provided significant improvement in symptoms of nasal polyposis compared to placebo, and in some cases offered benefits beyond what intranasal corticosteroid sprays achieved alone.¹¹ That makes leukotriene blockers a useful add-on for people with polyps who are not getting enough relief from steroids, particularly those who also have AERD or aspirin sensitivity.

Beyond the Lungs

Leukotrienes were initially studied almost exclusively in the context of airway disease, but research over the past two decades has linked them to inflammatory processes in organs far from the lungs.

Skin Conditions

In patients with eczema, levels of LTB4 and cysteinyl leukotrienes are elevated in both the blood and in skin lesions compared to healthy individuals.¹² Laboratory and clinical data have shown that leukotrienes contribute to inflammatory skin reactions more broadly, not just in allergic conditions but in diseases like psoriasis and urticaria as well.¹³ Despite this, leukotriene-modifying drugs are not typically prescribed as first-line treatments for skin disease. They tend to be considered when patients have overlapping conditions, like eczema alongside asthma, or when conventional treatments are not working.

Gut Inflammation

Inflammatory bowel disease (IBD) is another area where LTB4 shows up in excess. A study measuring leukotriene content in colon tissue found that people with IBD had roughly 50 times more LTB4 per gram of colon tissue than healthy controls.¹⁴ The combination of elevated LTB4 and the heavy neutrophil infiltration seen in IBD tissue is consistent with the known role of LTB4 as a neutrophil recruiter.¹⁵ Blocking the leukotriene pathway has shown promise in animal models of colitis, though it has not translated into mainstream IBD treatments in people yet.

Cardiovascular Disease

Atherosclerotic plaques are not just piles of cholesterol; they are active inflammatory sites, and leukotrienes contribute to the inflammation within them. A phase II trial involving patients with recent acute coronary syndrome found that a drug called atreleuton, which inhibits 5-lipoxygenase, reduced circulating LTB4 levels and, over six months of treatment, slowed the growth of arterial plaques and reduced the appearance of new ones compared to placebo.¹⁶ Computational studies have also suggested that existing leukotriene receptor antagonists like montelukast and zafirlukast may have cardioprotective effects through interactions with additional receptor targets.¹⁷ These are early-stage findings, but they illustrate why the cardiovascular field has been paying closer attention to leukotriene biology.

Neurodegeneration

Perhaps the most surprising frontier for leukotriene research is the brain. The 5-lipoxygenase enzyme and leukotriene receptors are present in brain tissue, and their signaling has been linked to multiple sclerosis, Alzheimer’s disease, and Parkinson’s disease.¹⁸ In mouse models of Alzheimer’s, blocking leukotrienes reduced neuroinflammation and improved cognitive function.¹⁹ The brain’s resident immune cells, microglia, appear to be a key source. When microglia are activated by toxins that mimic neurodegeneration, they ramp up 5-lipoxygenase expression and cysteinyl leukotriene production, and both zileuton (a 5-lipoxygenase inhibitor) and montelukast blocked this inflammatory response in cell experiments.²⁰ Whether this translates to meaningful neuroprotection in people remains an open question, but the preclinical evidence is strong enough that clinical trials are being designed.

Medications That Target Leukotrienes

There are two basic strategies for turning down the leukotriene signal. One is to block their production at the source by inhibiting the 5-lipoxygenase enzyme. Zileuton does this. The other is to block the receptor that cysteinyl leukotrienes bind to, so even if they are still being made, their message does not get through. Montelukast and zafirlukast take this second approach, targeting the CysLT1 receptor.

Structural studies have revealed that zafirlukast and pranlukast bind to the CysLT1 receptor in unusual ways, entering the binding pocket from the side through a gap between two parts of the receptor rather than from the top as many drugs do.²¹ This atypical binding mode may help explain why some patients respond well to one drug but not another, and why the drugs work better for certain people than for others. There is genuine variability in how effective these medications are across individuals, and researchers suspect that genetic differences in the receptor itself account for some of that.

Zileuton has a different limitation. Research into its metabolism found that a breakdown product of zileuton irreversibly binds to a protein in human blood, which may help explain rare cases of liver toxicity associated with the drug.²² Because of this risk, patients taking zileuton need periodic liver function monitoring, a hassle that has limited the drug’s popularity compared to the receptor blockers.

The Montelukast Black Box Warning

Montelukast is by far the most widely prescribed leukotriene modifier, used in millions of adults and children for asthma and allergies. In March 2020, the U.S. Food and Drug Administration required a boxed warning, the agency’s most serious label alert, regarding neuropsychiatric side effects including agitation, depression, sleep disturbances, and suicidal thinking.²³ The FDA acted on the basis of spontaneous adverse event reports that had accumulated over years of post-market surveillance.²⁴

The warning has understandably alarmed many parents, and the topic remains controversial among allergists and pulmonologists. The difficulty is separating signal from noise: montelukast is prescribed to enormous numbers of people, and some proportion of any large population will experience mood changes unrelated to their medication. Subsequent observational studies have reached mixed conclusions about whether montelukast actually causes neuropsychiatric harm at a population level or whether the association is inflated by reporting bias. Regardless of where the science eventually lands, the practical advice from the FDA is that clinicians should weigh the benefits against the risks for each individual patient and that patients (or their caregivers) should watch for mood or behavior changes after starting the drug.

Measuring Leukotrienes as a Diagnostic Tool

One practical application of leukotriene biology that has expanded significantly is using urinary leukotriene E4 (LTE4) as a biomarker. Because LTE4 is the stable end product of cysteinyl leukotriene metabolism, measuring it in urine gives a noninvasive snapshot of how much cysteinyl leukotriene your body is producing systemically.²⁵ Its uses have expanded beyond asthma severity to include evaluating environmental exposures, predicting aspirin sensitivity, screening for atopy in young children, and even assessing obstructive sleep apnea. Urinary LTE4 is also being explored as one of several mast cell mediators that can help clinicians diagnose mast cell activation syndromes, conditions where mast cells release inflammatory chemicals in excess.²⁶

The appeal of urinary LTE4 as a clinical tool is that it is cheap, easy to collect, and reflects whole-body production rather than a snapshot from a single tissue site. For clinicians trying to decide whether a patient might respond to a leukotriene modifier, elevated urinary LTE4 can tilt the decision toward trying one of these drugs, essentially identifying the patients whose inflammation is most driven by this particular pathway.

Omega-3 Fats and the Resolution Side of the Equation

Leukotrienes are pro-inflammatory, but the same enzyme family that makes them, the lipoxygenases, also produces molecules that actively shut inflammation down. When the body has adequate supplies of the omega-3 fatty acids EPA and DHA, those substrates get processed by 5-lipoxygenase and related enzymes into a class of molecules called specialized pro-resolving mediators, or SPMs. These include resolvins, protectins, and maresins, which promote the cleanup phase of inflammation: they signal immune cells to stop recruiting reinforcements, clear dead cells, and begin tissue repair.²⁷

In a study of healthy adults given an intravenous endotoxin challenge (a controlled way to trigger acute inflammation), pro-inflammatory eicosanoids like prostaglandins peaked within hours, while SPMs initially dipped and then rose at the 24-hour mark as the body shifted from the attack phase to the resolution phase.²⁸ This temporal pattern highlights how inflammation is supposed to work: a rapid onset driven by molecules like leukotrienes, followed by an organized wind-down driven by SPMs. When the resolution phase fails or is delayed, chronic inflammation takes hold.

The practical implication is not that eating salmon cures asthma. But a diet chronically low in omega-3s relative to omega-6s tips the substrate pool toward producing more pro-inflammatory leukotrienes and fewer resolving mediators. This does not mean supplementation will reliably fix inflammatory diseases, but it frames why dietary fat composition keeps coming up in conversations about chronic inflammation.

How Ancient Is This Pathway

Lipoxygenase enzymes, the machinery that makes leukotrienes, are not unique to mammals or even to animals. Lipoxygenase-like genetic sequences have been identified across all three domains of life: bacteria, archaea, and eukaryotes.²⁹ Whether archaea actually produce functional lipoxygenases is still uncertain, but the broad distribution suggests that lipid-based signaling through oxygenated fatty acids is extremely old in evolutionary terms. In plants, lipoxygenases produce jasmonates, signaling molecules involved in wound responses and pathogen defense. In humans, the same enzymatic logic got repurposed to run the inflammatory and immune signaling pathways we now associate with conditions like asthma and cardiovascular disease. The conservation of this enzyme family over billions of years hints at just how fundamental lipid-based chemical signaling is to cellular life.