The research team set out to address a well-known therapeutic gap. Proton pump inhibitors and H2-receptor antagonists reduce gastric acid and relieve symptoms, but they do little to halt the underlying inflammatory cascade and cellular damage that perpetuate injury and slow healing. Prolonged use of these drugs has been linked to hypomagnesemia, renal complications, and infections such as Clostridium difficile, while antibiotic resistance increasingly undermines eradication therapy for Helicobacter pylori, the other major cause of ulcer disease. Live probiotics have shown promise as mucosal protectants, but they raise safety concerns for immunocompromised patients and pose practical problems of shelf life, stability, and standardization. Paraprobiotics—inactivated microbial cells or their structural components—sidestep many of these issues while, according to accumulating evidence, retaining much of the immunomodulatory activity of their living counterparts.

To prepare the paraprobiotic, the researchers grew B. lactis BB-12 anaerobically, concentrated the cells, and heated the suspension at 85 degrees Celsius for 15 minutes. Flow cytometry using the SYTO 9 and propidium iodide dyes confirmed that the treatment was decisive: 99.5 percent of the bacterial population showed the propidium iodide-positive, membrane-compromised signature of dead cells, with fewer than 0.2 percent remaining viable. The washed, non-viable preparation therefore represented intact dead cells carrying their structural arsenal of peptidoglycans, teichoic acids, and surface-layer proteins—the components now recognized as the principal effectors of paraprobiotic bioactivity—rather than a soup of soluble metabolites.

The experiment used fifty adult male Balb/c mice divided into five groups of ten. One group served as healthy controls; a second received a single oral dose of indomethacin, a non-steroidal anti-inflammatory drug that reliably induces severe gastric ulceration by inhibiting protective prostaglandins; and three treatment groups received lansoprazole, live B. lactis BB-12, or the heat-killed paraprobiotic five minutes before the ulcer-inducing dose. Six hours later, the animals were sacrificed and their stomachs examined. The results were dramatic. Indomethacin alone left hemorrhagic lesions covering 52.5 percent of the gastric mucosa, with a macroscopic damage score near the maximum of four. Lansoprazole reduced the ulcer area to 15.1 percent, an inhibition of 71.2 percent. The live probiotic achieved 58.9 percent inhibition, and the paraprobiotic 67.0 percent—statistically indistinguishable from the drug at the level of ulcer area.

Where the paraprobiotic clearly pulled ahead was in damage severity. Its macroscopic damage score of 1.02 was significantly lower not only than that of untreated ulcer mice but also lower than the scores of both the lansoprazole group and the live probiotic group. Histological examination told the same story. Under the microscope, indomethacin had devastated the mucosa with deep necrosis, hemorrhage, vascular occlusion, edema, and dense neutrophil infiltration, producing a total damage index of 3.95. Lansoprazole lowered that index to 2.49, but the live probiotic and the paraprobiotic outperformed the drug, driving the index down to 1.27 and 0.95 respectively, with mucosal architecture largely preserved and inflammation minimal.

Biochemical analyses revealed how the treatments were shielding the tissue. Indomethacin severely depleted the stomach’s antioxidant defenses—superoxide dismutase, catalase, and reduced glutathione all fell sharply—while malondialdehyde, a marker of lipid peroxidation, surged. Both bacterial preparations restored the antioxidant enzymes to near-control levels and suppressed lipid peroxidation more effectively than lansoprazole did. Myeloperoxidase activity, a proxy for neutrophil infiltration, was similarly tamed. In the blood, the picture was one of systemic immune reprogramming: the cytokine storm of tumor necrosis factor-alpha and interleukin-6 triggered by indomethacin was damped most powerfully by the paraprobiotic, which outperformed both the drug and the live probiotic, while the anti-inflammatory cytokine interleukin-10, crushed by the ulcer-inducing drug, was fully restored by both bacterial treatments.

The centerpiece of the study, however, lay in its Western blot analysis of the PANoptosis pathway—a term coined in 2019 to describe a lytic cell death program that simultaneously engages pyroptosis, apoptosis, and necroptosis through a multi-protein complex called the PANoptosome. In the ulcerated stomachs, all three arms were firing at once. The NLRP3 inflammasome was upregulated, caspase-1 was cleaved into its active form, and its substrates—gasdermin D, which punches lethal pores in cell membranes, and interleukin-1β, which fans the inflammatory fire—were both processed at high levels, marking pyroptosis. The DNA sensor ZBP1 was elevated, caspase-8 and the executioner caspase-3 were activated, and gasdermin E was cleaved, a step thought to convert otherwise quiet apoptosis into inflammatory secondary necrosis. Finally, the necroptosis kinases RIPK3 and MLKL were heavily phosphorylated, indicating that the third death program had also been engaged.

All three treatments blunted this coordinated cell death response, but the bacterial preparations, and especially the paraprobiotic, were consistently the stronger inhibitors. The paraprobiotic suppressed cleaved caspase-1 and cleaved interleukin-1β significantly more than the live probiotic, showed the most potent anti-apoptotic effect on ZBP1 and caspase-3, and reduced phosphorylated RIPK3 more than lansoprazole. Because a therapy targeting only one death pathway might simply leave the others to finish the job, the authors argue that the paraprobiotic’s ability to simultaneously restrain NLRP3, ZBP1, and RIPK3 signaling makes it a broad-spectrum cell death regulator—one that intercepts stress signals at their source rather than downstream. This is, according to the researchers, the first evidence that gastric ulcer pathology is driven by this integrated death network and that a paraprobiotic can inhibit it.

The implications are considerable. A dead bacterial preparation that matches or beats a frontline drug, carries no risk of infection, resists storage and manufacturing pitfalls, and works through rapid mucosal interaction rather than long-term colonization could reshape how inflammatory gastrointestinal disease is prevented and treated. The authors are careful to note the limits of their work: the study used a single acute model, a single strain, and a six-hour window, and it examined key regulatory proteins rather than the full PANoptosome complex, which includes adaptors such as ASC and FADD. Whether the effect extends to ulcers caused by H. pylori or stress, and whether it holds in other species and in humans, remains to be shown. Still, the message is provocative: the protective power of a probiotic may not require the microbe to be alive at all—only intact enough for its surface molecules to talk the gut’s immune system out of destroying itself.

Subject of Research: Gastroprotective effects of heat-inactivated Bifidobacterium lactis BB-12 paraprobiotics against indomethacin-induced gastric ulcer through inhibition of PANoptosis

Article Title: Paraprobiotics Derived From Bifidobacterium animalis Subsp. Lactis BB‐12 Attenuates Indomethacin‐Induced Gastric Ulcer by Inhibiting the PANoptosis Pathway

Article References: Yavaş, A., Özkiran, E., & Akan, E. (2026). Paraprobiotics Derived From Bifidobacterium animalis Subsp. Lactis BB ‐12 Attenuates Indomethacin‐Induced Gastric Ulcer by Inhibiting the PANoptosis Pathway. Food Science & Nutrition, 14(10), Article e72397. https://doi.org/10.1002/fsn3.72397

Image Credits: AI Generated

DOI: 10.1002/fsn3.72397

Keywords: paraprobiotics, Bifidobacterium lactis BB-12, gastric ulcer, PANoptosis, pyroptosis, apoptosis, necroptosis, indomethacin, oxidative stress, NLRP3 inflammasome, probiotics, gastroprotection

The research, conducted by a team affiliated with Minia University in Egypt, set out to answer a deceptively simple question: does the color of your quinoa matter when it comes to protecting your gut? The investigators compared ordinary white quinoa against a tri-color blend combining white, red, and black seeds in a rat model of indomethacin-induced gastric injury. Their rationale rested on well-documented chemistry. Red and black quinoa varieties typically carry substantially higher total phenolic content and greater radical-scavenging capacity than the pale traditional grain, thanks to pigments such as anthocyanins and betalains. The team hypothesized that this richer phytochemical arsenal would translate into measurably better gastroprotection.

Three signature compounds anchored the mechanistic case. Procyanidin B2, an oligomeric proanthocyanidin, is known to scavenge reactive oxygen species, inhibit lipid peroxidation, and suppress the NF-κB inflammatory master switch. Cinchonain IB, a complex flavanol derivative, has been associated with cytokine modulation and tissue repair. Kaempferol-3-O-rutinoside, a common flavonol, may downregulate inducible nitric oxide synthase and COX-2 while reinforcing the gastric mucus barrier. Because the density of these molecules varies dramatically between quinoa varieties, the researchers reasoned that a head-to-head dietary trial could reveal whether phytochemical diversity directly determines therapeutic potency.

The experimental design was deliberately food-based rather than extract-based. Thirty-six male Sprague Dawley rats were randomly assigned to six groups of six, following the ethical 3Rs principle to minimize animal use. Baked bread was prepared from either refined wheat flour, flour containing 40 percent white quinoa powder, or flour containing 40 percent tri-color quinoa powder, then ground and blended into a standard rodent diet at a 25:75 ratio. Daily portions were weighed and remnants collected to verify that every rat consumed a statistically uniform 21 to 23 grams of food per day, ensuring that any differences in outcome reflected the grain itself rather than unequal intake. After 21 days of feeding, injury was induced with a single oral dose of 30 milligrams per kilogram of indomethacin.

The results were striking. Indomethacin alone devastated the stomachs of control rats: gastric pH plummeted from 3.93 to 1.66, malondialdehyde, a lipid peroxidation marker of oxidative damage, surged from 0.15 to 0.23 nanomoles per gram, and reduced glutathione, the tissue’s primary endogenous antioxidant, collapsed from 1.80 to 0.71 milligrams per gram. Both quinoa diets pushed these values back toward baseline, but the tri-color blend consistently outperformed the white variety. Most notably, malondialdehyde in the tri-color group fell to 0.14 nanomoles per gram, essentially restoring oxidative balance, while glutathione recovered to 1.30 milligrams per gram, a 72 percent restoration compared with roughly 56 percent for white quinoa.

Inflammation told a parallel story. Cyclooxygenase activity more than doubled in the indomethacin-only controls, reaching 5.20 units per milligram, and nuclear NF-κB p65 climbed from 1.62 to 3.81 micrograms per milliliter. Tri-color quinoa supplementation cut COX activity to 2.96 and NF-κB to 2.11, a 45 percent reduction relative to injured controls, with white quinoa trailing slightly behind. Pepsin activity, a measure of the digestive enzyme that can chew through a compromised mucosa, followed the same pattern. The authors attribute these effects to the tri-color blend’s presumed abundance of anthocyanins, betalains, procyanidins, and cinchonains, compounds that literature links to glutathione regeneration and suppression of inflammatory signaling.

Under the microscope, the differences became visually unmistakable. Blinded pathologists, scoring tissue independently with strong agreement, graded necrosis, edema, and inflammation on a zero-to-three scale. Injured control rats scored 2.4 for necrosis, 2.8 for edema, and 2.6 for inflammation, reflecting extensive mucosal destruction, inflammatory infiltration, and submucosal swelling. White quinoa roughly halved those scores, but tri-color quinoa reduced necrosis to 0.4, edema to 0.6, and inflammation to 0.5, an 83 percent drop in mucosal necrosis and near-complete preservation of the gastric architecture. Body weight told the same tale: indomethacin-treated controls gained only 39 grams over the study, while quinoa-fed injured rats gained 42 to 44 grams, indicating that the grain blunted the drug’s systemic as well as local toll.

To probe mechanism, the team turned to molecular docking against human crystal structures of the gastric proton pump Atp4a, COX-2, and NF-κB. Procyanidin B2 bound the proton pump with an affinity of minus 8.9 kilocalories per mole, outperforming the co-crystallized reference ligand and offering a theoretical basis for quinoa acting as a natural acid-secretion moderator. Cinchonain IB delivered the standout result at NF-κB, binding at minus 8.2 kilocalories per mole through hydrogen bonding with Lys417 and hydrophobic contact with Phe439, a mode resembling synthetic NF-κB inhibitors. The authors also note that baking may not destroy these compounds: internal crumb temperatures during standard baking hover around 95 to 98 degrees Celsius, and heat can even release bound phenolics into more bioaccessible forms, which helps explain why a bread-based intervention worked.

The study also raised gastric pH in treated animals, from 1.66 to 2.10 in the tri-color group, possibly through the buffering action of quinoa’s organic acids such as malate and citrate, and boosted mucin production, thickening the physical mucus barrier that stands between acid and epithelium. Together with the antioxidant and anti-inflammatory data, these findings sketch a coherent, multi-front defense: quinoa compounds simultaneously neutralize radicals, calm inflammatory transcription, buffer luminal acidity, and reinforce the mucus lining. The authors caution, however, that they could not perform chromatographic profiling of their specific extracts because the batch was exhausted, so attribution to individual compounds remains literature-based and suggestive rather than definitive.

The limitations are real. Only male rats were studied, leaving sex-specific responses unexplored; a single high-dose time point cannot capture the dynamics of long-term human consumption; and no human trial data exist yet. Still, the central message is compelling and unusually practical: the pigmented seeds of a climate-resilient Andean pseudocereal, eaten as ordinary bread, outprotected their paler counterpart against one of the most common drug side effects in medicine. If future chromatographic, dose-ranging, and clinical studies confirm the effect, tri-color quinoa could move from trendy salad topping to evidence-backed dietary ally for the millions of people who need daily NSAID relief but cannot afford to sacrifice their stomachs along the way.

Subject of Research: Gastroprotective effects of white and tri-color quinoa against NSAID-induced gastric injury

Article Title: Comparative Evaluation of White Quinoa and Tri‐Color Quinoa on Indomethacin‐Induced Gastrointestinal Damage

Article References: Alqahtani, N. S., Hassan, H. M., Mohamed, H. M., Gazaly, F. M., & Sadeek, R. A. (2026). Comparative Evaluation of White Quinoa and Tri‐Color Quinoa on Indomethacin‐Induced Gastrointestinal Damage. Food Science & Nutrition, 14(10), Article e72418. https://doi.org/10.1002/fsn3.72418

Image Credits: AI Generated

DOI: 10.1002/fsn3.72418

Keywords: quinoa, NSAIDs, indomethacin, gastric ulcer, gastroprotection, polyphenols, procyanidin B2, cinchonain IB, NF-κB, oxidative stress, functional foods, molecular docking

The clinical problem the researchers targeted is widespread. Non-steroidal anti-inflammatory drugs such as indomethacin relieve pain, fever, and inflammation, but they do so partly by inhibiting cyclooxygenase-1, an enzyme that helps produce the prostaglandins that keep the gastric mucosa healthy. Stripping away that protection leaves the stomach wall exposed to acid and pepsin, and indomethacin additionally ignites inflammatory signaling cascades that kill epithelial cells. Current countermeasures, chiefly proton pump inhibitors like omeprazole, suppress acid secretion by blocking the gastric H+/K+-ATPase, but long-term use of these drugs carries its own concerns, motivating the search for gentler, food-based alternatives.

Petasites japonicus offered an intriguing candidate. The plant has traditionally been used in East Asia for tension headaches and gastrointestinal spasms, and in Europe and North America for migraines, bronchial asthma, and seasonal allergic rhinitis. Its leaves and stems are rich in phenolic acids, including chlorogenic acid and fukinolic acid, along with several dicaffeoylquinic acid derivatives. To capture these compounds efficiently, the team reflux-extracted one kilogram of dried, ground plant material with either water or 50 percent aqueous ethanol at 50 degrees Celsius for five hours. High-performance liquid chromatography then quantified the phenolic content of each preparation.

The solvent choice mattered considerably. The 50 percent ethanol extract contained 42.48 milligrams of fukinolic acid per gram, compared with 25.35 milligrams in the water extract, while chlorogenic acid levels were nearly identical at roughly 13.5 milligrams per gram. Adding in the dicaffeoylquinic derivatives, the ethanol extract delivered a total polyphenol content of 80.21 milligrams per gram against 53.31 for water. On that chemical basis, the researchers selected the ethanol extract for all biological testing, reasoning that its richer phenolic payload would better represent the plant’s active potential.

In the laboratory, the extract proved strikingly protective. When human gastric adenocarcinoma AGS cells and Hs746T gastric carcinoma cells were exposed to 800 micromolar indomethacin for three hours, viability collapsed to 55.4 percent and 69.2 percent of control levels respectively. Pretreatment with the extract for one hour beforehand significantly blunted that damage, lifting viability to 71.9 percent in AGS cells at 50 micrograms per milliliter and 82.4 percent in Hs746T cells at 100 micrograms per milliliter. Crucially, the extract showed no cytotoxicity on its own across the entire 1 to 100 micrograms per milliliter range tested, and the researchers noted that dietary polyphenols naturally reach comparable concentrations in the gastric lumen before absorption.

Molecular analysis revealed three converging mechanisms. First, indomethacin sharply reduced MUC5AC, the predominant mucin glycoprotein that forms the stomach’s protective mucus barrier, dropping it to 0.65-fold in AGS cells and 0.48-fold in Hs746T cells; extract pretreatment restored those levels substantially. Second, the extract suppressed indomethacin-driven upregulation of acid secretion machinery, including the histamine H2 receptor gene HRH2 and subunits of the proton pump, ATP4A and ATP4B, which assemble into the H+/K+-ATPase that pumps acid into the stomach. Third, it dampened inflammation: indomethacin had boosted expression of inducible nitric oxide synthase and cyclooxygenase-2 and triggered phosphorylation of the transcription factor NF-κB and its inhibitor IκB-α, but the extract pulled all of these markers back down in a dose-dependent manner. Upstream, the extract also quieted the MAPK kinases ERK, JNK, and p38, whose indomethacin-induced phosphorylation reached as high as 8.24-fold in AGS cells before treatment brought it down.

The animal experiments translated these cellular findings into whole-body protection. Fifty male Sprague-Dawley rats were divided into control, indomethacin, omeprazole, and two extract-dose groups, with the test substances given orally once daily for seven days before a single 75 milligrams per kilogram dose of indomethacin. After quality-control exclusions, seven rats per group were analyzed. Macroscopic examination showed extensive hemorrhagic lesions in the indomethacin group, but the ulcer index fell to 0.58-fold at 50 milligrams per kilogram of extract and 0.40-fold at 100 milligrams per kilogram. Histological scoring told the same story: severe mucosal erosion, epithelial disruption, submucosal edema, and leukocyte infiltration in the indomethacin group scored 4.0, while extract treatment reduced the score to 1.3 and 0.7 at the two doses, with the lower dose matching omeprazole’s 1.3.

Tissue analyses confirmed the same molecular signature seen in culture. Indomethacin cut gastric MUC5AC protein to 0.58-fold of control, but extract restored it to 0.85-fold and 0.99-fold at the two doses. The drug raised Hrh2 mRNA to 3.28-fold and Atp4b to 1.16-fold; the higher extract dose brought these down to 1.88-fold and 0.85-fold respectively, the latter essentially matching control levels. Inflammatory chemistry followed suit: gastric nitric oxide rose from 3.52 to 5.86 micromolar under indomethacin and TNF-α from 1.39 to 1.98 picograms per milliliter, while extract treatment reduced both, and phosphorylated NF-κB, IκB-α, ERK, JNK, and p38 all declined dose-dependently in tissue lysates.

To probe how the plant’s signature compounds might act directly on drug targets, the team docked chlorogenic acid and fukinolic acid against the H+/K+-ATPase, the histamine H2 receptor, cyclooxygenase-2, and the TNF-α trimer, using omeprazole, cimetidine, and aspirin as reference ligands. The phenolic acids bound the proton pump through the residue Cys813 and the H2 receptor through Asp98, and their strongest predicted affinities came at cyclooxygenase-2, where chlorogenic acid scored −9.3 and fukinolic acid −9.0 kilocalories per mole, comfortably outperforming aspirin’s −6.7. Both compounds also showed moderate binding at the TNF-α trimer interface. The authors caution that docking is predictive and that the whole extract, not isolated compounds, produced the observed effects, with future work needed to isolate individual contributions.

The dose translation is perhaps the most striking practical detail. Applying US Food and Drug Administration body-surface-area conversion, the highest rat dose of 100 milligrams per kilogram corresponds to a human equivalent dose of 16.22 milligrams per kilogram, roughly 973 milligrams daily for a 60-kilogram adult. Based on the extraction yield, that amount equates to eating approximately 6.5 grams of fresh Petasites japonicus leaves and stems, an entirely ordinary dietary quantity. The authors acknowledge limitations, including the cancer-derived nature of the cell lines and the absence of direct measurements of gastric juice volume, pH, and acidity, and they call for follow-up studies using primary cells, gastric organoids, or pylorus-ligated models. Even so, the convergence of preserved mucus barriers, dampened acid-pump genes, and suppressed NF-κB and MAPK signaling across cells, rats, and simulations makes a compelling case that this everyday vegetable deserves attention as a functional food ingredient for protecting the stomach against painkiller injury.

Subject of Research: Gastroprotective effects of Petasites japonicus ethanol extract against NSAID-induced gastric ulcer

Article Title: Gastroprotective effects of a dietary Petasites japonicus ethanol extract against indomethacin-induced gastric injury via regulation of mucosal defense, acid secretion-related targets, and inflammation

Article References: Hwang, B., Hwang, S.-K., Kim, J.-Y., Song, J.-H., Son, Y.-J., Kim, H., Jung, W., Lee, J. J., Cho, S.-C., Chung, H., & Moon, S.-K. (2026). Gastroprotective effects of a dietary Petasites japonicus ethanol extract against indomethacin-induced gastric injury via regulation of mucosal defense, acid secretion-related targets, and inflammation. Journal of Agriculture and Food Research, 31, Article 103325. https://doi.org/10.1016/j.jafr.2026.103325

Image Credits: AI Generated

DOI: 10.1016/j.jafr.2026.103325

Keywords: Petasites japonicus, gastric ulcer, indomethacin, NSAIDs, MUC5AC, NF-κB, MAPK, proton pump, chlorogenic acid, fukinolic acid, functional food, gastroprotection

The clinical stakes are considerable. Bronchopulmonary dysplasia, defined by the need for supplemental oxygen or respiratory support at a corrected gestational age of thirty-six weeks, affects a substantial proportion of infants born before twenty-eight weeks of gestation and is associated with long-term respiratory morbidity, neurodevelopmental impairment, and rehospitalization throughout childhood. Its pathogenesis is multifactorial, involving inflammation, infection, hyperoxia exposure, impaired alveolar and vascular development, and genetic and environmental interactions. Because no single therapy has proven reliably protective, clinicians scrutinize every drug that reaches the developing lung for possible harm, and the analgesics and anti-inflammatory agents used in the first weeks of life are no exception.

The story of these drugs in the neonatal intensive care unit begins with the ductus arteriosus itself. Increased blood flow across a patent ductus arteriosus can be associated with increased pulmonary blood circulation and morbidity, a hemodynamic burden that physicians have tried to relieve since the latter part of the twentieth century by closing a hemodynamically significant ductus in the hope of improving outcomes. The pharmacological workhorses of that effort have been cyclooxygenase inhibitors, chiefly indomethacin and ibuprofen, which reduce prostaglandin signaling and allow the vessel to constrict and close. Both drugs have been used extensively for ductal closure, but both carry side effects and safety concerns in preterm infants, including effects on renal perfusion, gastrointestinal integrity, and platelet function, concerns that have driven a decades-long search for alternatives.

That search produced one of the more memorable accidental discoveries in modern neonatology. As recounted by Sharma and Bhandari, Hammerman and colleagues observed that the use of acetaminophen in preterm infants led to closure of the patent ductus arteriosus, a finding reported in case series that surprised many observers. The mechanism is plausible: acetaminophen acts on prostaglandin synthesis through pathways distinct from classical cyclooxygenase inhibition, and the ductus in the preterm infant remains sensitive to even modest reductions in prostaglandin activity. Following those initial case reports, multiple trials demonstrated that acetaminophen was as effective in closing the ductus as the two established non-steroidal anti-inflammatory drugs, ibuprofen and indomethacin. Crucially, those studies did not look only at closure rates; they also examined associated morbidities, and bronchopulmonary dysplasia emerged as the outcome of greatest interest.

The evidence on that outcome, however, has been reassuringly consistent so far. A large multicenter trial conducted by Gupta and colleagues, published in the New England Journal of Medicine, showed no significant difference in the incidence of bronchopulmonary dysplasia between groups of infants treated with ibuprofen and those given placebo. A retrospective study by Jensen and colleagues compared one group of infants receiving acetaminophen with another receiving ibuprofen or indomethacin and found that the incidence of death or grade 2 to 3 bronchopulmonary dysplasia was similar in both groups. These findings suggested that neither class of drug, when used for ductal closure, clearly worsens the risk of chronic lung disease, at least within the populations and dosing regimens studied.

The BeNeDuctus trial added an important dimension to this debate. This large multicenter randomized non-inferiority trial compared expectant management of a significant patent ductus arteriosus, meaning careful observation without immediate drug treatment, against early treatment with ibuprofen. The trial showed no difference in the incidence of bronchopulmonary dysplasia, necrotizing enterocolitis, or death between the two management strategies. That result was consequential in its own right, because it suggested that routine early pharmacological closure of the ductus may not be necessary for all affected infants. But it also created an unexpected opportunity: some patients in both subgroups received acetaminophen, not for ductal closure but for analgesia, meaning the trial inadvertently enrolled a cohort of extremely preterm infants exposed to the drug for reasons unrelated to their ductus.

Hoornenborg and colleagues exploited that opportunity in their secondary analysis, asking whether paracetamol given as an analgesic was associated with an increased risk of bronchopulmonary dysplasia in extremely preterm infants. The question matters because acetaminophen is among the most widely administered medications in neonatal intensive care, used for procedural and postoperative pain and increasingly considered for ductal closure. If the drug carried even a modest risk to the developing lung, the population-level consequences could be substantial given how many preterm infants receive it. Sharma and Bhandari frame their commentary around exactly this tension between therapeutic utility and pulmonary safety.

Concern about acetaminophen’s effects on the lung is not merely theoretical. Laboratory studies referenced in the commentary have shown that toxic acetaminophen exposure can induce distal lung endoplasmic reticulum stress, proinflammatory signaling, and emphysematous changes in the adult murine lung, and that the developing murine lung appears susceptible to acetaminophen toxicity in ways independent of the hepatic damage for which the drug is best known. Investigators have also raised the possibility that acetaminophen exposure in early life could have lifelong consequences for respiratory health. On the other side of the ledger, ibuprofen has its own pulmonary profile: animal work has documented vascular and pulmonary effects of ibuprofen on neonatal lung development, and recent studies indicate that inhibition of the mitochondrial integrated stress response can ameliorate ibuprofen-induced endothelial dysfunction in models of neonatal hyperoxia-induced lung injury. Both drug classes, in other words, have biological plausibility for lung effects that clinical trials have so far not translated into clear harm.

Interpreting this literature requires attention to the difficulty of the outcome itself. Bronchopulmonary dysplasia is now understood as a syndrome with multiple pulmonary phenotypes in the preterm infant, and its diagnosis has been refined through evidence-based approaches that grade severity by the level of respiratory support required. Newer tools, including magnetic resonance imaging phenotyping and life-course approaches to lung function monitoring after preterm birth, are reshaping how researchers detect subtle drug effects that survival-based or oxygen-based definitions may miss. The commentary’s authors, who have previously argued that bronchopulmonary dysplasia research must move from the bedside to the bench and back again, emphasize that postnatal inflammation, corticosteroid effects on lung development, and gene-environment interactions all complicate any attempt to isolate the contribution of a single analgesic or anti-inflammatory drug.

Where does this leave clinicians and families? The accumulating trial evidence, from the Gupta ibuprofen trial, the Jensen retrospective comparison, the BeNeDuctus trial, and now the Hoornenborg secondary analysis, points toward a consistent conclusion: neither acetaminophen nor the classical non-steroidal anti-inflammatory drugs, as used in contemporary neonatal practice, has been shown to increase the incidence of bronchopulmonary dysplasia or death in extremely preterm infants. At the same time, Sharma and Bhandari’s commentary underscores that the question of pulmonary safety has not been closed as definitively as the ductus itself. Preclinical signals of lung toxicity, the heterogeneity of bronchopulmonary dysplasia phenotypes, and the possibility of long-term respiratory consequences all argue for continued vigilance. As randomized trials of prophylactic acetaminophen for ductal closure and expectant management strategies continue to mature, the developing lung remains the outcome against which every neonatal drug must ultimately be judged.

Subject of Research: Pulmonary safety of acetaminophen and NSAID treatment for patent ductus arteriosus in preterm infants

Article Title: Does use of acetaminophen and/or NSAIDs increase the risk of developing bronchopulmonary dysplasia?

Article References: Sharma, R., & Bhandari, V. (2026). Does use of acetaminophen and/or NSAIDs increase the risk of developing bronchopulmonary dysplasia?. Pediatric Research. https://doi.org/10.1038/s41390-026-05526-y

Image Credits: AI Generated

DOI: 10.1038/s41390-026-05526-y

Keywords: bronchopulmonary dysplasia, acetaminophen, NSAIDs, patent ductus arteriosus, preterm infants, BeNeDuctus trial, neonatology, ibuprofen, indomethacin, Pediatric Research, lung development, neonatal intensive care