Why Creatine Reaches the Lungs
Creatine is usually discussed as a muscle supplement, and the bulk of the research supports that framing. The International Society of Sports Nutrition (ISSN) position stand from 2017 describes creatine as one of the most popular ergogenic aids available, notes that supplementation reliably raises muscle creatine stores, and summarises a large safety literature across many populations (Kreider and colleagues, 2017). What most people do not realise is that creatine does not stay in muscle. It circulates in the blood and is taken up by other tissues, including the lungs, and that is where a less familiar line of research begins.
The research described in this article comes from a conference talk by Professor Rodolfo de Paula Vieira, who introduces himself as a professor at the Evangelical University of Goiás in Brazil and states that he has no disclosures related to the presentation. Vieira led the first animal studies on creatine and asthma during his PhD at the University of São Paulo, and his later work covers lung injury models. His talk is unusual because it presents both sides of the story: situations where creatine appears to make a lung problem worse, and situations where it appears to protect the lung.
Vieira opens with a 2001 study by Ipsiroglu and colleagues, published in Life Sciences, that measured creatine content in various tissues of animals before and after oral creatine monohydrate. According to Vieira, lung tissue normally holds very little creatine, but after supplementation the creatine content of the lungs rose sharply. He treats this as the first demonstration that an oral creatine supplement physically reaches lung tissue, which is the premise behind everything that follows. If creatine were simply absent from the lungs, there would be no reason to expect it to affect lung inflammation in either direction.
Early Cell Studies
The next pieces of the puzzle came from cell culture experiments. Vieira points to a 2003 paper that tested creatine on human pulmonary endothelial cells, the cells lining the blood vessels of the lung. Nomura and colleagues, publishing in the British Journal of Pharmacology, stimulated these cells with serotonin and hydrogen peroxide (H2O2), both of which are mediators involved in several lung diseases. They found that 5 millimolar creatine suppressed the leakiness of the endothelial layer caused by those stimuli, reduced the expression of the adhesion molecules ICAM1 and E selectin, and reduced the sticking of neutrophils to endothelial cells (Nomura and colleagues, 2003). Vieira highlights neutrophil adhesion in particular, since it is an early and essential step in almost every inflammatory process.
A 2006 study by Sestili and colleagues in Free Radical Biology and Medicine then asked whether creatine could protect living cells from oxidative damage. The team exposed human promonocytic cells, human endothelial cells, and mouse myoblasts to hydrogen peroxide, tert butyl hydroperoxide, and in one cell line peroxynitrite. Vieira notes that these oxidants are relevant to the biology of COPD, asthma, cystic fibrosis, idiopathic pulmonary fibrosis, and acute respiratory distress syndrome. Creatine at concentrations from 0.1 to 10 millimolar reduced the cytotoxic effects of the oxidants in all the cell lines tested, and the degree of protection tracked the amount of creatine inside the cells. Importantly, the protection was not explained by higher activity of antioxidant enzymes such as catalase and glutathione peroxidase. The authors concluded that creatine exerts a mild but significant antioxidant effect in living cells through direct scavenging of reactive oxygen and nitrogen species (Sestili and colleagues, 2006).
Two cautions apply here. First, these were dishes of cells, not lungs in a living animal, and a concentration in a culture dish does not translate neatly into a scoop of powder. Second, the Sestili group themselves described the antioxidant effect as mild. Even so, the combination of these two papers set up a reasonable hypothesis: if creatine calms inflammation in lung lining cells and buffers oxidative stress, it might help in asthma, a disease driven by chronic airway inflammation.
The Mouse Asthma Experiments
Vieira describes asthma as the second most common chronic respiratory disease in the world. The World Health Organization estimates that asthma affected about 363 million people in 2023, caused roughly 442,000 deaths, and is the most common chronic disease among children (WHO, 2024). The rationale for studying creatine in asthma had an extra layer: asthma is unusually common in athletes, and many athletes use creatine. Reviews of elite sport consistently report higher rates of asthma and exercise induced bronchoconstriction than in the general population, with estimates that vary widely by sport, from around 10 to 50 percent in some analyses and as high as 55 percent in others depending on the study population and diagnostic criteria (Frontiers in Allergy, 2022; Journal of Functional Morphology and Kinesiology, 2024). Nobody had tested what creatine does in an allergic lung, so Vieira set out to find out.
The resulting paper was published in 2007 in the American Journal of Respiratory Cell and Molecular Biology under the title Creatine supplementation exacerbates allergic lung inflammation and airway remodeling in mice (Vieira and colleagues, 2007). The design used 31 male Balb/c mice in four groups: untreated controls, creatine alone, an asthma model induced with ovalbumin (OVA), and the asthma model plus creatine. Ovalbumin is an egg protein used to sensitise mice so that their airways mount an allergic response. According to Vieira, the OVA groups received intraperitoneal injections of ovalbumin on several days during the protocol and were then exposed to an aerosol of 1 percent ovalbumin from day 21 to day 53. Creatine was given over the same window, from day 21 to day 53, at 0.5 grams per kilogram per day.
The researchers measured a long list of outcomes. Airway hyperresponsiveness was assessed with whole body plethysmography while the mice inhaled rising concentrations of methacholine, a drug that constricts the bronchi. Blood levels of IgE and IgG1, two antibody markers of allergy, were recorded. Cells in bronchoalveolar lavage fluid (fluid washed out of the airways) were counted and typed. In lung tissue, the team quantified eosinophils, the density of cells expressing IL4, IL5, IL2, interferon gamma and insulin like growth factor 1 (IGF1), plus collagen, elastic fibres and airway smooth muscle thickness. IL4 and IL5 are T helper 2 (Th2) cytokines that drive allergic inflammation, interferon gamma and IL2 are Th1 cytokines that counterbalance it, and IGF1 is a growth factor involved in smooth muscle growth.
The first surprise was lung function. Vieira explains that the mice given creatine alone, with no allergen at all, started from a higher baseline level of bronchoconstriction and developed hyperresponsiveness to methacholine that approached the level seen in the asthma group. When creatine was added to the asthma model, baseline constriction stayed high and hyperresponsiveness was greater still. In his words, creatine was clearly modulating or impairing lung function, at least in mice.
The inflammation data were more nuanced. In lavage fluid, creatine did not raise total cell counts, neutrophils, or mononuclear cells, and creatine alone did not significantly raise eosinophils. In the combined group, however, eosinophils in lavage fluid were much higher than in the asthma group. Eosinophils are the signature cell of allergic airway inflammation, so this mattered. Antibody levels told a different story: creatine alone did not raise IgE or IgG1, and it did not raise them further in sensitised mice either. Vieira draws attention to this because it means creatine was not making the mice more allergic in the classic sense; it was amplifying what happened downstream in the airway.
Tissue analysis sharpened the picture. In the airway wall, creatine alone raised eosinophil numbers to roughly the same level as the asthma model, and the combined group showed an exacerbation. Lymphocytes and macrophages were increased in both creatine groups. Among the cytokines, creatine alone did not increase IL4, but the combined group showed more IL4 positive cells than the asthma group. IL5, which drives eosinophil production and recruitment, was raised by creatine alone to nearly the asthma level and exacerbated in the combined group. IGF1 followed the same pattern, with the combined group showing roughly twice the expression seen in asthma alone. The published abstract confirms that creatine in sensitised mice increased hyperresponsiveness, eosinophilic inflammation, the density of IL4, IL5 and IGF1 positive cells, airway collagen and elastin, and smooth muscle thickness (Vieira and colleagues, 2007).
The remodelling findings are the part Vieira stresses most. Airway remodelling is the structural change that develops in longstanding asthma: collagen and elastic fibres accumulate in the airway wall, and the smooth muscle grows thicker through both hypertrophy and hyperplasia. Current reviews agree that remodelling is linked to worse outcomes, persistent airflow obstruction, and poor treatment response, and that existing therapies mainly target inflammation rather than the structural changes themselves, with limited effect on remodelling (Archivos de Bronconeumología, 2024). Vieira goes further and says there is no effective treatment for remodelling, which is a stronger statement than most reviews make, but the direction is the same. In his mice, creatine alone produced collagen deposition comparable to the asthma model, and the combined group showed even more. Elastic fibres increased with creatine alone but were not further increased in the combined group. Smooth muscle thickness increased with creatine alone to near asthma levels and was exacerbated in the combined group. Histological signs of bronchoconstriction were present in asthma and not worsened by creatine.
The authors concluded that creatine supplementation amplified the effects of allergen sensitisation, increasing airway inflammation, remodelling and hyperresponsiveness through Th2 and IGF1 pathways. They were explicit that how far results from a mouse model of allergic airway inflammation can be transferred to people with asthma was unclear. That caveat deserves emphasis. The dose of 0.5 grams per kilogram per day is large relative to typical human maintenance intakes of 3 to 5 grams per day, although converting doses between mice and humans is not a simple matter of body weight, and the mice were young, sedentary, and genetically identical.
Airway Epithelium and Mucus
Having shown that creatine worsened the asthma phenotype, Vieira’s group wanted to know which cells were responsible. The airway epithelium, the layer of cells lining the bronchi, had become a central player in asthma research, so the team repeated the same protocol and focused on epithelial markers. The results were published in 2010 in the International Journal of Sports Medicine as Creatine activates airway epithelium in asthma (Ferreira and colleagues, 2010).
Lavage findings matched the earlier study: creatine did not raise total cells but did raise eosinophils and lymphocytes. This time the team also counted bronchial epithelial cells in the lavage fluid, because finding epithelial cells washed out of the airway suggests the epithelium is being injured. Vieira says they were present.
The epithelium itself was examined in detail. Goblet cells, which produce mucus, rose as a percentage of the epithelium with creatine alone to the same level as the asthma model, and rose further in the combined group. Ciliated cells, which clear the airway, fell similarly in all three treated groups. Neutral mucus production was not increased by creatine alone but was raised in the asthma model and remained high in the combined group; acid mucus did not change in any group.
Cytokine expression in the epithelium produced a mixed pattern that Vieira reports candidly. IL4 rose in asthma and was not exacerbated by creatine. IL5 was strongly induced by creatine alone, even above the asthma group, and the combined group was no different from creatine alone. IL13, another Th2 cytokine that stimulates mucus production, was not increased by creatine alone, rose in asthma, and was not exacerbated. The chemokine CCL11, which attracts eosinophils, rose equally with creatine alone and in asthma but, for reasons the authors could not explain, not in the combined group. CCL5 was highest in asthma. CCL2, which attracts T lymphocytes, was strongly induced by creatine alone to the asthma level but again not in the combined group.
Adhesion molecules and inflammatory signalling followed suit. ICAM1 rose with creatine alone to the asthma level with no further increase in the combined group; VCAM1 rose in asthma and the combined group without exacerbation. Inducible nitric oxide synthase (iNOS), which is involved in nearly all inflammatory processes, was induced by creatine alone to asthma levels and exacerbated in the combined group. NF kappa B, a master switch for inflammatory gene expression, was induced by creatine alone, was much higher in asthma, and in the combined group sat at the same level as creatine alone.
Growth factors and matrix enzymes were measured because they regulate remodelling. VEGF did not change in any group. TGF beta was induced by creatine alone to the asthma level but not significantly in the combined group. In this study, epithelial IGF1 was not raised by creatine alone, although it rose in asthma and the combined group without exacerbation; this differs from the earlier finding of increased IGF1 in inflammatory cells, which is a reminder that the two studies looked at different cell compartments. EGF receptor rose in asthma and was not exacerbated. TIMP1 rose in all three treated groups equally, TIMP2 rose in asthma and the combined group, MMP9 (which degrades collagen) rose with creatine alone to the asthma level without exacerbation, and MMP12 (which degrades elastic fibres) rose only in asthma.
The authors concluded that creatine upregulates the inflammatory cascade and the remodelling process in a model of asthma, largely by activating airway epithelial cells. The honest reading of the data is that creatine alone switched on several epithelial inflammatory markers to a degree resembling the allergic model, but the combination with allergen did not consistently produce additive effects, and several results, such as CCL11 and CCL2, went in a direction the researchers could not explain.
Exercise Changes the Picture
One of the most practically important parts of the talk is a study Vieira mentions only briefly. His group tested whether regular aerobic exercise changes the effect of creatine in the same mouse model. The paper, Exercise reduces effects of creatine on lung, appeared in the International Journal of Sports Medicine in 2009 (Vieira and colleagues, 2009). Six groups were used, including creatine with low intensity exercise and the asthma model with creatine and low intensity exercise. In sensitised mice receiving creatine, adding low intensity aerobic exercise reduced eosinophils in lavage fluid and in the airways, reduced the density of IL4 and IL5 positive cells, reduced airway collagen and elastic fibres, reduced smooth muscle thickness, and lowered the bronchoconstriction index, all compared with the asthma plus creatine group.
Vieira summarises the finding simply: in the asthma model without exercise, creatine exacerbates the asthma phenotype, but when regular aerobic exercise is added, five times per week in his description, the exacerbating effects disappear and only the beneficial effects of creatine remain. The published abstract supports the first half of that statement, since every measured outcome improved relative to the creatine plus asthma group. Whether the exacerbating effect was abolished entirely, rather than reduced, is a stronger claim than the abstract makes, and readers should treat it as the speaker’s interpretation. It fits with a broader literature from the same group showing that aerobic training reduces allergic airway inflammation and remodelling in mice on its own.
This matters for interpretation because the mice in the 2007 and 2010 studies were sedentary. Most people who take creatine do so because they train. The animal data therefore describe a scenario, creatine without exercise, that applies to fewer supplement users than it might first appear.
Lung Injury and Transplant Models
The second half of the talk turns to a completely different kind of lung problem, and the effect of creatine flips. Ischemia and reperfusion injury occurs when blood flow to an organ is cut off and then restored, which is unavoidable during organ transplantation and some lung surgery. During ischemia, oxidative phosphorylation fails and ATP stores fall, contributing to cell death. When blood returns, the damaged cells release a burst of free radicals and cytokines while growth factor levels fall, and toll like receptors sit at the centre of this response. In the lung, the result can be acute lung injury or acute respiratory distress syndrome (ARDS), which Vieira characterises as severe hypoxaemic failure with bilateral inflammation and oedema, loss of compliance, no cardiac pressure abnormality, and intense neutrophil driven inflammation both in the lung and systemically.
The reasoning for testing creatine here drew on earlier work showing that creatine raises IGF1 in muscle and lung, modulates toll like receptors in macrophages, and reduces ischemic injury in brain and heart models. The hypothesis was that creatine given beforehand could blunt lung injury from ischemia and reperfusion. The study was published in 2016 in the Journal of Heart and Lung Transplantation (Almeida and colleagues, 2016), which Vieira notes was the highest impact journal in transplantation at the time.
Male Wistar rats were divided into four groups: sham surgery, sham plus creatine, ischemia and reperfusion, and creatine plus ischemia and reperfusion. Creatine was given for 5 days at 0.5 grams per kilogram per day by gavage before 90 minutes of left pulmonary artery ischemia and 120 minutes of reperfusion. According to the published abstract, creatine reduced total cells and neutrophils in lavage fluid and in the circulation, inhibited pulmonary oedema as judged by total proteins in lavage fluid and a histological oedema index, reduced neutrophil accumulation in lung tissue, reduced caspase 3 expression, reduced toll like receptor 4, and increased toll like receptor 7 in lung tissue (Almeida and colleagues, 2016).
Vieira adds detail from the slides. Ischemia and reperfusion raised tissue elastance and resistance, which are measures of how stiff and obstructed the lung has become, and pre supplementation with creatine prevented those increases both at the end of reperfusion and afterwards. Exhaled nitric oxide rose with injury and was held down by creatine. He describes protection of about 90 percent for total proteins in lavage fluid, complete protection against oedema, around 50 percent reduction in systemic leukocytes and neutrophils, complete prevention of the rise in serum IL1 beta, and roughly 90 to 100 percent inhibition of caspase 3 in the airway epithelium and vessel walls, which he reads as evidence that creatine was preventing cell death. These percentages are the speaker’s descriptions of his data; the published abstract confirms the direction and statistical significance of these effects but the magnitudes should be read as his summary rather than independently checked figures.
IGF1 appears here with the opposite meaning from the asthma studies. Vieira is careful to point out that IGF1 drives harmful remodelling in asthma but is protective in ischemia and reperfusion, and in the rat study creatine maintained IGF1 levels in both the epithelium and the vessels. Toll like receptor 4 is pro inflammatory and rises with injury severity; creatine suppressed it. Toll like receptor 7 is described as anti inflammatory; creatine increased it and partially restored it after injury. The group’s follow up work extended the finding to an actual lung transplant model in rats, where donor animals received creatine for 5 days before their lungs were stored in cold ischemia for 90 or 180 minutes and then transplanted. Treated animals showed better lung mechanics, better blood gases, lower exhaled nitric oxide, and less inflammation in blood, lavage fluid and lung tissue (Almeida and colleagues, 2020).
The clinical relevance is real but still distant. Primary graft dysfunction caused by ischemia and reperfusion remains a major limit on the success of lung transplantation, and the rat work raises the possibility of a cheap, well tolerated pretreatment for organ donors. No human trial of this idea has been published as far as the sources consulted for this article show, so it remains a promising lead rather than a treatment.
Human Evidence on Creatine and Lungs
Everything above comes from cells, mice and rats. What do we know about human lungs? The honest answer is: not much, and the little that exists points in different directions depending on the condition.
The only published trial designed to test the airway safety of creatine in athletes was published in 2019 in Medicine and Science in Sports and Exercise by Simpson, Kippelen and colleagues (Simpson and colleagues, 2019). The researchers cited Vieira’s mouse work as the reason for the study and noted that similar inflammatory and remodelling features had been seen in bronchial biopsies of elite athletes. Nineteen elite soccer players aged 16 to 21 completed a stratified, randomised, double blind, placebo controlled trial. The creatine group took 0.3 grams per kilogram per day for one week and then 5 grams per day for 7 weeks, a standard loading and maintenance protocol, while the placebo group took matching doses of maltodextrin. Airway inflammation was assessed by fractional exhaled nitric oxide (FeNO) and bronchial responsiveness by a dry air hyperpnoea challenge, with atopy checked by skin prick testing.
The result was a trend rather than a finding. FeNO changed unfavourably in the creatine group only, with a mean rise of 9 parts per billion against a fall of 5 in the placebo group, but the interaction did not reach statistical significance (P equal to 0.056), and the effect size was medium to large. The authors concluded that, on the basis of those trends, an adverse effect of creatine on the airways of elite athletes could not be excluded, particularly in those with allergic sensitisation. This is a small study with 9 people in the creatine arm, and a borderline P value in a small study is a reason to run a bigger one, not a verdict. It is nevertheless the only human data that speak directly to Vieira’s concern, and it leans the same way.
The other human data come from COPD, which is not an allergic disease. A 2005 trial in Thorax randomised 38 COPD patients to creatine or placebo during pulmonary rehabilitation and found increases in fat free mass, peripheral muscle strength and endurance, and health status, but no improvement in exercise capacity (Fuld and colleagues, 2005). A larger follow up trial in 2008, with 100 patients randomised and 80 completing, found that creatine did not add anything to the substantial benefits of rehabilitation, even though muscle biopsies confirmed the creatine had been taken up (Deacon and colleagues, 2008). Neither trial reported harm to lung function, which is modestly reassuring, but neither was designed to detect subtle changes in airway inflammation, and COPD patients are not a model for allergic asthma.
Finally, the broad safety literature summarised in the ISSN position stand covers kidney and liver markers, hydration, cramping and similar concerns across hundreds of studies and finds a favourable safety profile; airway inflammation is not among the risks it singles out (Kreider and colleagues, 2017). That absence reflects the fact that nobody had looked carefully, rather than evidence that the lungs are unaffected.
Practical Takeaways for Asthma and Supplement Users
Vieira closes with three messages, and they are a fair summary of the evidence as it stands. First, creatine supplementation actively interacts with lung function and with the pulmonary immune response; it is not inert in the lung. Second, creatine taken without regular physical exercise may exacerbate the allergic asthma phenotype, with the word may doing real work because the finding comes from mice. Third, in the context of pulmonary ischemia and reperfusion, creatine shows a strong protective effect in animals, including preservation of lung function and mechanics.
For readers deciding what to do with this, a few points follow directly from the sources. The evidence that creatine worsens allergic airway inflammation is consistent across two mouse studies and one small human trial, but all of it is preliminary, the mouse doses were high, and the mice were sedentary. The one animal study that added exercise found that aerobic training reduced every measured harmful effect. People with diagnosed allergic asthma who are considering creatine have a reasonable basis to discuss it with their clinician, to keep their asthma well controlled before starting, and to pay attention to symptoms or exhaled nitric oxide measurements if those are available to them. People without asthma or allergic sensitisation have no human evidence of lung harm to weigh, and the COPD trials, while not designed to answer the question, did not flag any.
The protective findings in lung injury are the more exciting part of the talk scientifically, but they are also the furthest from application. They apply to a specific surgical scenario, they come from rats, and they involved a short course of creatine given before a planned injury. Nothing in them suggests that everyday creatine use protects the lungs of healthy people, and nothing in them should be read as a reason to take creatine for a lung condition without a doctor’s involvement.
Honest labelling matters here. The evidence rating for this article is early, because the central claims rest on animal data and a single underpowered human trial, and because the two halves of the story point in opposite directions depending on the type of lung problem. Larger human trials in athletes with allergic sensitisation, and ideally trials that include an exercise arm, would settle the asthma question. Until then, the most accurate statement is the one Vieira’s own 2007 paper made: the extent to which these results can be transposed to patients with asthma is unclear.