The leukotriene B4 /BLT1-dependent neutrophil accumulation exacerbates immune complex-mediated glomerulonephritis.

Crescent formation is the most important pathological finding that defines the prognosis of nephritis. Although neutrophils are known to play an important role in the progression of crescentic glomerulonephritis, such as anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis, the key chemoattractant for neutrophils in ANCA-associated glomerulonephritis has not been identified. Here, we demonstrate that a lipid chemoattractant, leukotriene B4 (LTB4 ), and its receptor BLT1 are primarily involved in disease pathogenesis in a mouse model of immune complex-mediated crescentic glomerulonephritis. Circulating neutrophils accumulated into glomeruli within 1 h after disease onset, which was accompanied by LTB4 accumulation in the kidney cortex, leading to kidney injury. LTB4 was produced by cross-linking of Fc gamma receptors on neutrophils. Mice deficient in BLT1 or LTB4 biosynthesis exhibited suppressed initial neutrophil infiltration and subsequent thrombotic glomerulonephritis and renal fibrosis. Depletion of neutrophils before, but not after, disease onset prevented proteinuria and kidney injury, indicating the essential role of neutrophils in the early phase of glomerulonephritis. Administration of a BLT1 antagonist before and after disease onset almost completely suppressed induction of glomerulonephritis. Finally, we found that the glomeruli from patients with ANCA-associated glomerulonephritis contained more BLT1-positive cells than glomeruli from patients with other etiologies. Taken together, the LTB4 -BLT1 axis is the key driver of neutrophilic glomerular inflammation, and will be a novel therapeutic target for the crescentic glomerulonephritis.

Lysophosphatidic acid receptor1/3 antagonist inhibits the activation of satellite glial cells and reduces acute nociceptive responses.

Lysophosphatidic acid (LPA) exerts various biological activities through six characterized G protein-coupled receptors (LPA1-6 ). While LPA-LPA1  signaling contributes toward the demyelination and retraction of C-fiber and induces neuropathic pain, the effects of LPA-LPA1  signaling on acute nociceptive pain is uncertain. This study investigated the role of LPA-LPA1  signaling in acute nociceptive pain using the formalin test. The pharmacological inhibition of the LPA-LPA1 axis significantly attenuated formalin-induced nociceptive behavior. The LPA1  mRNA was expressed in satellite glial cells (SGCs) in dorsal root ganglion (DRG) and was particularly abundant in SGCs surrounding large DRG neurons, which express neurofilament 200. Treatment with LPA1/3 receptor (LPA1/3 ) antagonist inhibited the upregulation of glial markers and inflammatory cytokines in DRG following formalin injection. The LPA1/3 antagonist also attenuated phosphorylation of extracellular signal-regulated kinase, especially in SGCs and cyclic AMP response element-binding protein in the dorsal horn following formalin injection. LPA amounts after formalin injection to the footpad were quantified by liquid chromatography/tandem mass spectrometry, and LPA levels were found to be increased in the innervated DRGs. Our results indicate that LPA produced in the innervated DRGs promotes the activation of SGCs through LPA1 , increases the sensitivity of primary neurons, and modulates pain behavior. These results facilitate our understanding of the pathology of acute nociceptive pain and demonstrate the possibility of the LPA1 on SGCs as a novel target for acute pain control.

Isoflurane attenuates sepsis-associated lung injury.

Acute lung injury is one of major complications associated with sepsis, responsible for morbidity and mortality. Patients who suffer from acute lung injury often require respiratory support under sedations, and it would be important to know the role of sedatives in lung injury. We examined volatile anesthetic isoflurane, which is commonly used in surgical setting, but also used as an alternative sedative in intensive care settings in European countries and Canada. We found that isoflurane exposure attenuated neutrophil recruitment to the lungs in mice suffering from experimental polymicrobial abdominal sepsis. We found that isoflurane attenuated one of major neutrophil chemoattractants LTB4 mediated response via its receptor BLT1 in neutrophils. Furthermore, we have shown that isoflurane directly bound to BLT1 by a competition assay using newly developed labeled BLT1 antagonist, suggesting that isoflurane would be a BLT1 antagonist.

Dietary intake of n-3 polyunsaturated fatty acids alters the lipid mediator profile of the kidney but does not attenuate renal insufficiency.

The efficacy of n-3 polyunsaturated fatty acids (PUFAs) in improving outcomes in a renal ischemia-reperfusion injury (IRI) model has previously been reported. However, the underlying mechanisms remain poorly understood and few reports demonstrate how dietary n-3 PUFAs influence the composition of membrane phospholipids in the kidney. Additionally, it has not been elucidated whether perilla oil (PO), which is mainly composed of the n-3 alpha-linolenic acid, mitigates renal IRI. In this study, we investigated the effect of dietary n-3 PUFAs (PO), compared with an n-6 PUFA-rich soybean oil (SO) diet, on IRI-induced renal insufficiency in a rat model. Levels of membrane phospholipids containing n-3 PUFAs were higher in the kidney of PO-rich diet-fed rats than the SO-rich diet-fed rats. Levels of blood urea nitrogen and serum creatinine were significantly higher in the ischemia-reperfusion group than the sham group under both dietary conditions. However, no significant differences were observed in blood urea nitrogen, serum creatinine, or histological damage between PO-rich diet-fed rats and SO-rich diet-fed rats. In the kidney of PO-rich diet-fed rats, levels of arachidonic acid and arachidonic acid-derived pro-inflammatory lipid mediators were lower than SO-rich diet-fed rats. Eicosapentaenoic acid and eicosapentaenoic acid-derived lipid mediators were significantly higher in the kidney of PO-rich than SO-rich diet-fed rats. These results suggest that dietary n-3 PUFAs alter the fatty acid composition of membrane phospholipids and lipid mediators in the kidney; however, this does not attenuate renal insufficiency or histological damage in a renal IRI model.

Prostaglandin E2 and its receptor EP2 trigger signaling that contributes to YAP-mediated cell competition.

Cell competition is a biological process by which unfit cells are eliminated from "cell society." We previously showed that cultured mammalian epithelial Madin-Darby canine kidney (MDCK) cells expressing constitutively active YAP were eliminated by apical extrusion when surrounded by "normal" MDCK cells. However, the molecular mechanism underlying the elimination of active YAP-expressing cells was unknown. Here, we used high-throughput chemical compound screening to identify cyclooxygenase-2 (COX-2) as a key molecule triggering cell competition. Our work shows that COX-2-mediated PGE2 secretion engages its receptor EP2 on abnormal and nearby normal cells. This engagement of EP2 triggers downstream signaling via an adenylyl cyclase-cyclic AMP-PKA pathway that, in the presence of active YAP, induces E-cadherin internalization leading to apical extrusion. Thus, COX-2-induced PGE2 appears a warning signal to both abnormal and surrounding normal cells to drive cell competition.

Leukotriene B4 receptor 1 exacerbates inflammation following myocardial infarction.

Leukotriene B4 receptor 1 (BLT1), a high-affinity G-protein-coupled receptor for leukotriene B4 (LTB4 ), is expressed on various inflammatory cells and plays critical roles in several inflammatory diseases. In myocardial infarction (MI), various inflammatory cells are known to be recruited to the infarcted area, but the function of BLT1 in MI is poorly understood. Here, we investigated the role of BLT1 in MI and the therapeutic effect of a BLT1 antagonist, ONO-4057, on MI. Mice with infarcted hearts showed increased BLT1 expression and LTB4 levels. BLT1-knockout mice with infarcted hearts exhibited attenuated leukocyte infiltration, proinflammatory cytokine production, and cell death, which led to reduced mortality and improved cardiac function after MI. Bone-marrow transplantation studies showed that BLT1 expressed on bone marrow-derived cells was responsible for the exacerbation of inflammation in infarcted hearts. Furthermore, ONO-4057 administration attenuated the inflammatory responses in hearts surgically treated for MI, which resulted in reduced mortality and improved cardiac function after MI. Our study demonstrated that BLT1 contributes to excessive inflammation after MI and could represent a new therapeutic target for MI.

Leukotriene A4 hydrolase deficiency protects mice from diet-induced obesity by increasing energy expenditure through neuroendocrine axis.

Obesity is a health problem worldwide, and brown adipose tissue (BAT) is important for energy expenditure. Here, we explored the role of leukotriene A4 hydrolase (LTA4 H), a key enzyme in the synthesis of the lipid mediator leukotriene B4 (LTB4 ), in diet-induced obesity. LTA4 H-deficient (LTA4 H-KO) mice fed a high-fat diet (HFD) showed a lean phenotype, and bone-marrow transplantation studies revealed that LTA4 H-deficiency in non-hematopoietic cells was responsible for this lean phenotype. LTA4 H-KO mice exhibited greater energy expenditure, but similar food intake and fecal energy loss. LTA4 H-KO BAT showed higher expression of thermogenesis-related genes. In addition, the plasma thyroid-stimulating hormone and thyroid hormone concentrations, as well as HFD-induced catecholamine secretion, were higher in LTA4 H-KO mice. In contrast, LTB4 receptor (BLT1)-deficient mice did not show a lean phenotype, implying that the phenotype of LTA4 H-KO mice is independent of the LTB4 /BLT1 axis. These results indicate that LTA4 H mediates the diet-induced obesity by reducing catecholamine and thyroid hormone secretion.

Metabolism and biological functions of 12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid.

12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid (12-HHT) is a 17-carbon hydroxy fatty acid that is biosynthesized either by enzymatic pathways, like thromboxane synthase (TXAS) and cytochrome P450 or a non-enzymatic pathway. TXAS catalyzes the isomerization reaction from PGH2 to 12-HHT, malondialdehyde, and TXA2 at a ratio of 1:1:1. Furthermore, 12-HHT has been considered as a mere byproduct of TXA2 biosynthesis, and its biological function has long been uncertain. BLT2 was initially identified as a low-affinity leukotriene B4 (LTB4) receptor, which is also activated by various hydroxy-eicosatetraenoic acids (HETEs), suggesting that BLT2 may be activated by other endogenous ligands apart from LTB4 and HETEs. By unbiased ligand screening using crude lipids from rat organs, 12-HHT has been identified as an endogenous agonist for BLT2. The 12-HHT-BLT2 axis induces mast cell migration and contributes to allergic inflammation. BLT2 is also expressed in epithelial cells of the small intestine and skin in mice and contributes to in vivo epithelial barrier functions.

The role of propofol hydroxyl group in 5-lipoxygenase recognition.

Propofol is a clinically important intravenous anesthetic. We previously reported that it directly inhibited 5-lipoxygenase (5-LOX), a key enzyme for leukotriene biosynthesis. Because the hydroxyl group in propofol (propofol 1-hydroxyl) is critical for its anesthetic effect, we examined if its presence would be inevitable for 5-lipoxygenase recognition. Fropofol is developed by substituting the hydroxy group in propofol with fluorine. We found that propofol 1-hydroxyl was important for 5-lipoxygenase recognition, but it was not absolutely necessary. Azi-fropofol bound to 5-LOX at one of the two propofol binding sites of 5-LOX (pocket around Phe-187), suggesting that propofol 1-hydroxyl is important for 5-LOX inhibition at the other propofol binding site (pocket around Val-431). Interestingly, 5-hydroperoxyeicosatetraenoic acid (5-HpETE) production was significantly increased by stimulation with calcium ionophore A23187 in HEK293 cells expressing 5-LOX, suggesting that the fropofol binding site is important for the conversion from 5-HpETE to leukotriene A4. We also indicated that propofol 1-hydroxyl might have contributed to interaction with wider targets among our body.

Na+-mimicking ligands stabilize the inactive state of leukotriene B4 receptor BLT1.

Most G-protein-coupled receptors (GPCRs) are stabilized in common in the inactive state by the formation of the sodium ion-centered water cluster with the conserved Asp2.50 inside the seven-transmembrane domain. We determined the crystal structure of the leukotriene B4 (LTB4) receptor BLT1 bound with BIIL260, a chemical bearing a benzamidine moiety. Surprisingly, the amidine group occupies the sodium ion and water locations, interacts with D662.50, and mimics the entire sodium ion-centered water cluster. Thus, BLT1 is fixed in the inactive state, and the transmembrane helices cannot change their conformations to form the active state. Moreover, the benzamidine molecule alone serves as a negative allosteric modulator for BLT1. As the residues involved in the benzamidine binding are widely conserved among GPCRs, the unprecedented inverse-agonist mechanism by the benzamidine moiety could be adapted to other GPCRs. Consequently, the present structure will enable the rational development of inverse agonists specific for each GPCR.

Volatile anesthetics isoflurane and sevoflurane directly target and attenuate Toll-like receptor 4 system.

General anesthesia has been the requisite component of surgical procedures for over 150 yr. Although immunomodulatory effects of volatile anesthetics have been growingly appreciated, the molecular mechanism has not been understood. In septic mice, the commonly used volatile anesthetic isoflurane attenuated the production of 5-lipoxygenase products and IL-10 and reduced CD11b and intercellular adhesion molecule-1 expression on neutrophils, suggesting the attenuation of TLR4 signaling. We confirmed the attenuation of TLR4 signaling in vitro and their direct binding to TLR4-myeloid differentiation-2 (MD-2) complex by photolabeling experiments. The binding sites of volatile anesthetics isoflurane and sevoflurane were located near critical residues for TLR4-MD-2 complex formation and TLR4-MD-2-LPS dimerization. Additionally, TLR4 activation was not attenuated by intravenous anesthetics, except for a high concentration of propofol. Considering the important role of TLR4 system in the perioperative settings, these findings suggest the possibility that anesthetic choice may modulate the outcome in patients or surgical cases in which TLR4 activation is expected.-Okuno, T., Koutsogiannaki, S., Hou, L., Bu, W., Ohto, U., Eckenhoff, R. G., Yokomizo, T., Yuki, K. Volatile anesthetics isoflurane and sevoflurane directly target and attenuate Toll-like receptor 4 system.

The volatile anesthetic sevoflurane reduces neutrophil apoptosis via Fas death domain-Fas-associated death domain interaction.

Sepsis remains a significant health care burden, with high morbidities and mortalities. Patients with sepsis often require general anesthesia for procedures and imaging studies. Knowing that anesthetic drugs can pose immunomodulatory effects, it would be critical to understand the impact of anesthetics on sepsis pathophysiology. The volatile anesthetic sevoflurane is a common general anesthetic derived from ether as a prototype. Using a murine sepsis model induced by cecal ligation and puncture surgery, we examined the impact of sevoflurane on sepsis outcome. Different from volatile anesthetic isoflurane, sevoflurane exposure significantly improved the outcome of septic mice. This was associated with less apoptosis in the spleen. Because splenic apoptosis was largely attributed to the apoptosis of neutrophils, we examined the effect of sevoflurane on FasL-induced neutrophil apoptosis. Sevoflurane exposure significantly attenuated apoptosis. Sevoflurane did not affect the binding of FasL to the extracellular domain of Fas receptor. Instead, in silico analysis suggested that sevoflurane would bind to the interphase between Fas death domain (DD) and Fas-associated DD (FADD). The effect of sevoflurane on Fas DD-FADD interaction was examined using fluorescence resonance energy transfer (FRET). Sevoflurane attenuated FRET efficiency, indicating that sevoflurane hindered the interaction between Fas DD and FADD. The predicted sevoflurane binding site is known to play a significant role in Fas DD-FADD interaction, supporting our in vitro and in vivo apoptosis results.-Koutsogiannaki, S., Hou, L., Babazada, H., Okuno, T., Blazon-Brown, N., Soriano, S. G., Yokomizo, T., Yuki, K. The volatile anesthetic sevoflurane reduces neutrophil apoptosis via Fas death domain-Fas-associated death domain interaction.

Dietary ω-3 fatty acids alter the lipid mediator profile and alleviate allergic conjunctivitis without modulating Th2 immune responses.

Allergic conjunctivitis (AC) is one of the most common ocular surface diseases in the world. In AC, T helper type 2 (Th2) immune responses play central roles in orchestrating inflammatory responses. However, the roles of lipid mediators in the onset and progression of AC remain to be fully explored. Although previous reports have shown the beneficial effects of supplementation of ω-3 fatty acids in asthma or atopic dermatitis, the underlying molecular mechanisms are poorly understood. In this study, a diet rich in ω-3 fatty acids alleviated AC symptoms in both early and late phases without affecting Th2 immune responses, but rather by altering the lipid mediator profiles. The ω-3 fatty acids completely suppressed scratching behavior toward the eyes, an allergic reaction provoked by itch. Although total serum IgE levels and the expression levels of Th2 cytokines and chemokines in the conjunctiva were not altered by ω-3 fatty acids, eosinophil infiltration into the conjunctiva was dramatically suppressed. The levels of ω-6-derived proinflammatory lipid mediators, including those with chemoattractant properties for eosinophils, were markedly reduced in the conjunctivae of ω-3 diet-fed mice. Dietary ω-3 fatty acids can alleviate a variety of symptoms of AC by altering the lipid mediator profile.-Hirakata, T., Lee, H.-C., Ohba, M., Saeki, K., Okuno, T., Murakami, A., Matsuda, A., Yokomizo, T. Dietary ω-3 fatty acids alter the lipid mediator profile and alleviate allergic conjunctivitis without modulating Th2 immune responses.

Eicosanoids in Skin Wound Healing.

Wound healing is an important process in the human body to protect against external threats. A dysregulation at any stage of the wound healing process may result in the development of various intractable ulcers or excessive scar formation. Numerous factors such as growth factors, cytokines, and chemokines are involved in this process and play vital roles in tissue repair. Moreover, recent studies have demonstrated that lipid mediators derived from membrane fatty acids are also involved in the process of wound healing. Among these lipid mediators, we focus on eicosanoids such as prostaglandins, thromboxane, leukotrienes, and specialized pro-resolving mediators, which are produced during wound healing processes and play versatile roles in the process. This review article highlights the roles of eicosanoids on skin wound healing, especially focusing on the biosynthetic pathways and biological functions, i.e., inflammation, proliferation, migration, angiogenesis, remodeling, and scarring.

The Role of Leukotrienes as Potential Therapeutic Targets in Allergic Disorders.

Leukotrienes (LTs) are lipid mediators that play pivotal roles in acute and chronic inflammation and allergic diseases. They exert their biological effects by binding to specific G-protein-coupled receptors. Each LT receptor subtype exhibits unique functions and expression patterns. LTs play roles in various allergic diseases, including asthma (neutrophilic asthma and aspirin-sensitive asthma), allergic rhinitis, atopic dermatitis, allergic conjunctivitis, and anaphylaxis. This review summarizes the biology of LTs and their receptors, recent developments in the area of anti-LT strategies (in settings such as ongoing clinical studies), and prospects for future therapeutic applications.

Altered eicosanoid production and phospholipid remodeling during cell culture.

The remodeling of PUFAs by the Lands cycle is responsible for the diversity of phospholipid molecular species found in cells. There have not been detailed studies of the alteration of phospholipid molecular species as a result of serum starvation or depletion of PUFAs that typically occurs during tissue culture. The time-dependent effect of cell culture on phospholipid molecular species in RAW 264.7 cells cultured for 24, 48, or 72 h was examined by lipidomic strategies. These cells were then stimulated to produce arachidonate metabolites derived from the cyclooxygenase pathway, thromboxane B2, PGE2, and PGD2, and the 5-lipoxygenase pathway, leukotriene (LT)B4, LTC4, and 5-HETE, which decreased with increasing time in culture. However, the 5-lipoxygenase metabolites of a 20:3 fatty acid, LTB3, all trans-LTB3, LTC3, and 5-hydroxyeicosatrienoic acid, time-dependently increased. Molecular species of arachidonate containing phospholipids were drastically remodeled during cell culture, with a new 20:3 acyl group being populated into phospholipids to replace increasingly scarce arachidonate. In addition, the amount of TNFα induced by lipopolysaccharide stimulation was significantly increased in the cells cultured for 72 h compared with 24 h, suggesting that the remodeling of PUFAs enhanced inflammatory response. These studies supported the rapid operation of the Lands cycle to maintain cell growth and viability by populating PUFA species; however, without sufficient n-6 fatty acids, 20:3 n-9 accumulated, resulting in altered lipid mediator biosynthesis and inflammatory response.

Profiling of bioactive lipids in different dendritic cell subsets using an improved multiplex quantitative LC-MS/MS method.

Lipids are an energy source and key components of the cell membrane; however, they are also bioactive mediators of physiological and pathophysiological phenomena. Quantification of bioactive lipids is not easy because they have diverse chemical properties and are present in trace amounts. Here, we improved a multiplex method of quantifying bioactive lipids, thereby enabling measurement of 90 compounds simultaneously. We then used this system to quantify bioactive lipids produced by two subsets of dendritic cells (DCs): all-trans retinoic acid-treated DCs (RA-DCs) (a type of tolerogenic DC (tDC)) and conventional DCs (cDCs). We found that cDCs produced inflammatory lipid mediators such as leukotrienes, whereas RA-DCs produced anti-inflammatory lipid mediators such as prostaglandin I2. Consistent with this, cDCs expressed larger amounts of mRNA encoding 5-lipoxygenase and LTA4 hydrolase (both responsible for leukotriene biosynthesis) and RA-DCs produced larger amounts of mRNA encoding prostaglandin I2 synthase. Taken together, the results suggest that the method is useful for clarifying the roles of bioactive lipids during immune responses.

Endurance exercise training and high-fat diet differentially affect composition of diacylglycerol molecular species in rat skeletal muscle.

Insulin resistance of peripheral muscle is implicated in the etiology of metabolic syndrome in obesity. Although accumulation of glycerolipids, such as triacylglycerol and diacylglycerol (DAG), in muscle contributes to insulin resistance in obese individuals, endurance-trained athletes also have higher glycerolipid levels but normal insulin sensitivity. We hypothesized that the difference in insulin sensitivity of skeletal muscle between athletes and obese individuals stems from changes in fatty acid composition of accumulated lipids. Here, we evaluated the effects of intense endurance exercise and high-fat diet (HFD) on the accumulation and composition of lipid molecular species in rat skeletal muscle using a lipidomic approach. Sprague-Dawley female rats were randomly assigned to three groups and received either normal diet (ND) in sedentary conditions, ND plus endurance exercise training, or HFD in sedentary conditions. Rats were fed ND or HFD between 4 and 12 wk of age. Rats in the exercise group ran on a treadmill for 120 min/day, 5 days/wk, for 8 wk. Soleus muscle lipidomic profiles were obtained using liquid chromatography/tandem mass spectrometry. Total DAG levels, particularly those of palmitoleate-containing species, were increased in muscle by exercise training. However, whereas the total DAG level in the muscle was also increased by HFD, the levels of DAG molecular species containing palmitoleate were decreased by HFD. The concentration of phosphatidylethanolamine molecular species containing palmitoleate was increased by exercise but decreased by HFD. Our results indicate that although DAG accumulation was similar levels in trained and sedentary obese rats, specific changes in molecular species containing palmitoleate were opposite.

Intravenous anesthetic propofol binds to 5-lipoxygenase and attenuates leukotriene B4 production.

Propofol is an intravenous anesthetic that produces its anesthetic effect, largely via the GABAA receptor in the CNS, and also reduces the N-formyl-methionyl-leucyl-phenylalanine (fMLP)-induced neutrophil respiratory burst. Because fMLP-stimulated neutrophils produce leukotriene (LT)B4, we examined the effect of propofol on LTB4 production in vivo and in vitro Cecal ligation and puncture surgery was performed in mice, with or without exposure to propofol. Propofol attenuated the production of 5-lipoxygenase (5-LOX)-related arachidonic acid (AA) derivatives in the peritoneal fluid. Also, in the in vitro experiments on fMLP-stimulated neutrophils and 5-LOX-transfected human embryonic kidney cells, propofol attenuated the production of 5-LOX-related AA derivatives. Based on these results, we hypothesized that propofol would directly affect 5-LOX function. Using meta-azi-propofol (AziPm), we photolabeled stable 5-LOX protein, which had been used to solve the X-ray crystallographic structure of 5-LOX, and examined the binding site(s) of propofol on 5-LOX. Two propofol binding pockets were identified near the active site of 5-LOX. Alanine scanning mutagenesis was performed for the residues of 5-LOX in the vicinity of propofol, and we evaluated the functional role of these pockets in LTB4 production. We demonstrated that these pockets were functionally important for 5-LOX activity. These two pockets can be used to explore a novel 5-LOX inhibitor in the future.-Okuno, T., Koutsogiannaki, S., Ohba, M., Chamberlain, M., Bu, W., Lin, F.-Y., Eckenhoff, R. G., Yokomizo T., Yuki, K. Intravenous anesthetic propofol binds to 5-lipoxygenase and attenuates leukotriene B4 production.

Urinary prostaglandin D2 metabolite excretion during the first six months of life was significantly lower in breast-fed than formula-fed infants.

AIM: The metabolic changes that occur during the postnatal weaning period appear to be particularly important for future health, and breast milk is considered to provide the optimal source of infant nutrition. This pilot study from September 2013 to May 2015 examined the effect of breastfeeding on prostaglandin metabolism in healthy term infants. METHODS: Urine samples were collected from 19 infants at one month of age in the Juntendo University Hospital, Tokyo, Japan. The 13 infants in the breast-fed group received less than 540 mL/week of their intake from formula, and the other six were exclusively fed on formula. At six months, we sampled 14 infants: nine breast-fed and five receiving formula. The infants were from normal single pregnancies and free from perinatal complications. We analysed urinary prostaglandin metabolites-tetranor prostaglandin E2 metabolite (t-PGEM) and tetranor prostaglandin D2 metabolite (t-PGDM)-using liquid chromatography tandem-mass spectrometry. RESULTS: Urinary t-PGDM excretion at one and six months was significantly lower in breast-fed infants than formula-fed infants. However, urinary t-PGEM excretion at one and six months was not significantly different between the groups. CONCLUSION: Our study showed that the type of feeding in early infancy affected prostaglandin metabolism in healthy term infants.