Epinephrine effect on arachidonic acid biosynthesis in isolated adrenocortical cells

The in vivo and in vitro effect of epinephrine on the incorporation and desaturation of [1-14C]eicosa-8,11,14-trienoic acid was studied in isolated adrenocortical cells of rats. Control cells incubated at different substrate concentrations and for different periods of time were able to incorporate eicosatrienoic acid and to desaturate it to arachidonic acid. The ultrastructural study demonstrated that most of the cells belonged to the zona fasciculata and presented a good preservation. When the cells were isolated from rats killed 7 and 12 h after the administration of a single dose of epinephrine, a decrease in the incorporation and desaturation of 20:3n6 was observed. The effect on the desaturation was independent from the incorporation of the acid, and it was also observed in the microsomes of the decapsulated adrenal gland from rats treated with epinephrine. The fine structure of adrenocortical cells did not show changes after the treatment with epinephrine. The addition of the hormone to the incubation medium containing cells isolated from untreated rats produced no effect on arachidonic acid biosynthesis, indicating that the effect of epinephrine would be indirect, through either a metabolic or a hormone mediator.     

Omeprazole, cimetidine, and ranitidine: inhibition of acid production in isolated human parietal cells

The antisecretory properties of omeprazole, cimetidine, and ranitidine were studied in vitro, using human gastric mucosal cells, which were obtained by sequential pronase and collagenase incubation of small tissue specimens obtained by endoscopic biopsy. Acid production was measured as the accumulation of radioactive aminopyrine in the acid compartments of the parietal cells. Acid production was stimulated via H2-receptors by histamine (10(-4) M or 5 X 10(-6) M) and via intracellular mechanisms by db-cAMP (10(-3) M). Omeprazole induced a dose-dependent inhibition of acid production for all stimulators (IC50 = 2 X 10(-7) M and 3 X 10(-8) M with high and low concentrations of histamine, respectively, and 5 X 10(-6) M with db-cAMP). The H2-receptor antagonists dose-dependently inhibited the histamine-stimulated acid production (IC50 for cimetidine = 10(-5) M and 10(-6) M and for ranitidine = 10(-5) M and 2 X 10(-7) M for high and low concentrations of histamine, respectively). Neither cimetidine nor ranitidine inhibited acid production after intracellular stimulation with db-cAMP. Omeprazole reduced the aminopyrine accumulation stimulated by histamine (10(-4) M) already within 5-10 min, whereas cimetidine (10(-3) M and ranitidine (10(-4) M) required 20-30 min. The unstimulated level of acid production was also inhibited by omeprazole but not by the H2-receptor antagonists.     

生长抑素抑制酸分泌的机制研究

目的探讨生长抑素-14(SS-14)通过何种受体亚型抑制兔离体壁细胞组胺诱导的酸分泌.方法利用经纯化的离体壁细胞为研究模型,以14C-氨基比林摄取为指标,观察SS-14及某些生长抑素受体亚型特异性激动剂对组胺诱导的酸分泌的影响;用反转录聚合酶链反应方法(RT-PCR)及原位杂交方法(ISH)研究壁细胞生长抑素受体亚型的表达.结果SS-14、奥曲肽以及生长抑素Ⅱ型受体特异性激动剂NC8-12(10-9～10-7mol/L)均能明显抑制组胺(10-6mol/L)诱导的酸分泌(P《0.01),而生长抑紊Ⅲ、Ⅳ型受体激动剂在相同浓度下对组胺诱导的酸分泌无明显抑制作用(P》0.05);RTPCR方法扩增出了生长抑素Ⅱ型受体(SSR2)的特异片段;用ISH方法确定了离心涂片的壁细胞以及胃黏膜冰冻组织切片的壁细胞上有SSR2基因表达.结论在国内外首次证明SSR2介导生长抑素对兔离体壁细胞组胺诱导的酸分泌的抑制作用;首次证明壁细胞有SSP2的基因表达.     

Leukotrienes C4 and D4 potentiate acid production by isolated rat parietal cells

The effects of leukotrienes (LTs) B4, C4, and D4 on acid production by enriched (80%-85%) rat parietal cells were investigated. Acid production was indirectly measured by [14C]aminopyrine uptake into the cells. Leukotriene B4 (10(-10)-10(-6) mol/L) had no effect on basal or prestimulated [14C]aminopyrine uptake. Leukotriene C4 and LTD4 (10(-10)-10(-6) mol/L) also did not change basal acid production but potentiated prestimulated [14C]aminopyrine uptake. Maximal effects were observed with 1 x 10(-7) mol/L LTC4 or with 3 x 10(-7) mol/L LTD4. At these concentrations LTC4 and LTD4 induced the indicated increases above the responses to the following prestimulants (= 100%): 10(-4) mol/L histamine (71% and 74%, respectively), 10(-5) mol/L forskolin (54% and 106%), 10(-4) mol/L dibutyryl cyclic adenosine monophosphate (34% and 81%), and 10(-4) mol/L carbamylcholine (160% and 116%). Yet, adenosine triphosphate (2.5-5 x 10(-3) mol/L)-induced [14C]aminopyrine uptake in digitonin-permeabilized parietal cells was not further increased by LTC4 or LTD4. At 10(-5) mol/L the selective LTD4 antagonist L-660,711 (MK-571) reduced the effect of 3 x 10(-7) mol/L LTD4 by 74% but had no effect on the potentiation by LTC4. We conclude that the sulfidopeptide LTs C4 and D4, but not LTB4, exert a direct effect on rat parietal cells, and that this effect seems to be mediated by separate specific receptors. Leukotriene C4 and LTD4 potentiate prestimulated H+ formation by interacting with an intracellular mechanism that is commonly activated upon occupation of histamine H2- as well as muscarinic receptors, and that is also activated by the postreceptor stimuli forskolin and dibutyryl cyclic adenosine monophosphate; yet, this mechanism seems to be localized proximal to the H+,K+-adenosine triphosphatase.     

The pharmacologic modulation of the release of arachidonic acid metabolites from purified human lung mast cells

Although cyclooxygenase and lipoxygenase inhibitors have been widely used in studies of allergic and inflammatory disorders, the effect of these agents has not been determined on mediators released from purified human lung mast cells. The release of histamine, prostaglandin D2, leukotriene C4, leukotriene B isomers, 5-hydroxyeicosatetraenoic acid (5-HETE), and free arachidonic acid (AA) from preparations of purified human lung mast cells (90 +/- 2% pure) prelabeled with 3H-AA as modified by indomethacin, eicosatriynoic acid (ETI), and diethylcarbamazine (DEC) was determined. Indomethacin (3 microM) markedly (greater than 90%) inhibited the anti-IgE- and ionophore A23187-induced release of PGD2 from these cells but had no effect on the release of histamine or other AA metabolites. Specifically, no increase in LTC production was noted, and no large amount of shunting of products into those produced by lipoxygenases was noted. The ETI, a lipoxygenase inhibitor in many systems, inhibited the release of histamine, PGD2, LTC, LTB isomers, 5-HETE, and free AA, all with an IC50 between 3 and 10 microM. The lack of specificity for lipoxygenase products together with a similar potency for inhibition of histamine release suggests that ETI may act at an early event in the activation process of these cells, apparently prior to the action of phospholipase(s), which releases AA from cellular stores. The DEC inhibited PGD2 release in purified mast cells and histamine release in pure and crude preparations of mast cells, both with IC50 values ranging from 1 to 3 mM. No specificity for enzymes responsible for the production of LTA4 was observed in these cells, unlike the results reported in other systems.(ABSTRACT TRUNCATED AT 250 WORDS)     

幽门螺杆菌及其培养上清液粗提蛋白对兔离体胃壁细胞酸分泌的影响

目的 通过研究幽门螺杆菌(Hp)及其培养上清液粗提蛋白(BCF-P)对兔离体胃壁细胞酸分泌的影响,探讨Hp感染引起宿主胃酸分泌状态改变的可能机制.方法 兔胃体黏膜经Ⅰ型胶原酶消化、离心淘洗后获得新鲜分离的壁细胞,并进行短期培养.提取Hp培养上清液粗提蛋白(BCF-P)并进行真空干燥浓缩,HeLa细胞以中性红摄取试验鉴定其细胞空泡活性.兔离体壁细胞与Hp及BCF-P(100μg/ml)分别共孵育2、16 h和1、12 h,应用14C-氨基比林(14C-AP)摄取法测定Hp和BCF-P对组胺(1.0×10-4 mol/L)刺激的壁细胞酸分泌的影响;同时应用RT-PCR方法分析Hp和BCF-P对壁细胞H+-K+ ATP酶α亚基mRNA表达的影响.结果 (1)BCF-P中含有细胞空泡毒素(VacA),对HeLa细胞表现出细胞空泡活性.(2)与Hp共孵育2 h和16 h均能抑制组胺刺激的壁细胞酸分泌(P<0.05),抑制作用随孵育时间延长而增强,2 h抑制率为81%,16 h为94%;BCF-P作用1 h和12 h,均能抑制壁细胞酸分泌(P<0.05),抑制作用也随孵育时间延长而增强,1 h抑制率为24%,12 h为58%.(3)尽管与Hp孵育2 h能上调壁细胞H+-K+ATP酶α亚基mRNA表达(P<0.05),但孵育16 h则表现为下调其表达(P<0.05);BCF-P作用1 h和12 h,均抑制H+-K+ATP酶α亚基mRNA的表达(P<0.05).结论 Hp及其分泌的VacA可能通过下调壁细胞H+-K+ ATP酶表达水平来抑制组胺刺激的壁细胞酸分泌.     

兰索拉唑对离体壁细胞酸分泌的影响

目的应用兔离体壁细胞为模型,研究兰索拉唑体外抑酸效果.方法应用细胞淘洗与连续密度梯度离心相结合的方法分离兔胃黏膜壁细胞,以14C氨基比林摄取为酸分泌指标,观察西咪替丁及兰索拉唑对离体壁细胞组胺诱导的酸分泌的影响.结果壁细胞纯度达80%以上进行实验,兰索拉唑能明显抑制离体壁细胞组胺诱导的酸分泌,对组胺刺激酸分泌的50%抑制量(IC50)为9.59×10-8mol/L,明显高于H2受体拮抗剂(3.70×10-5mol/L).结论兰索拉唑对兔离体壁细胞组胺诱导的酸分泌具明显的抑制作用,效果优于西咪替丁;本研究为国内开展新的抑酸剂基础与临床研究提供了新方法.     

Role of arachidonic acid metabolites in hypoxic contractions of isolated porcine pulmonary artery and vein

Recently it has been proposed that hypoxic pulmonary vasoconstriction (HPV) is mediated by local release of sulfidopeptide leukotriene products of the lipoxygenase pathway of arachidonic acid metabolism. In the present study the response to reduced oxygen supply of isolated porcine lobar pulmonary artery and pulmonary vein spiral strips has been studied. Contractions of the pulmonary artery (mean maximum tension 66.9 +/- 13.0 mg, n = 10) required an increase in baseline tone of the preparation followed by exposure to anoxia (mean bath PO2 O +/- 3 mm Hg), whereas contractions of the pulmonary vein (mean maximum tension 75.2 +/- 13.3 mg, n = 10) could be elicited in response to hypoxia alone (mean bath PO2 40 +/- 4 mm Hg). Indomethacin (5.6 microM), a cyclooxygenase inhibitor, attenuated the arterial contraction, but the mechanism may have been independent of the cyclooxygenase pathway since phenidone, an inhibitor of both cyclooxygenase and lipoxygenase pathways, had no effect. Inhibition by FPL 55712, a leukotriene end-organ antagonist, was achieved only at a high concentration (20 microM). In the case of the pulmonary vein, both indomethacin and phenidone inhibited the contractile response, whereas FPL 55712 had no effect. Contractile responses to reduced oxygen supply can be induced in isolated porcine pulmonary artery and vein strips, but probably are not mediated by leukotrienes.     

Phospholipase activation and arachidonic acid release in isolated intestinal epithelial cells

A novel method for studying the mobilization of free arachidonic acid (AA) in isolated intestinal epithelial cells is described. The method is based on labeling the cellular phospholipids with 14C-AA and studying the release of this 14C-AA on subsequent phospholipase activation. Cells of high viability were isolated from the small intestine of guinea pigs and incubated with 14C-AA for 2 h; most of the incorporated 14C-AA was then esterified into phosphatidylethanolamine and phosphatidylcholine. When the labeled cells were stimulated with the calcium ionophore A23187 in the presence of external calcium, they released significant amounts of AA. In contrast, the cells released no AA when stimulated with A23187 in the absence of external calcium or in the presence of chlorpromazine or 4-bromophenacyl bromide, both of which are known to inhibit phospholipase A2 activity. On the other hand, the cells released significant AA in response to exogenous phospholipase C from Clostridium perfringens. These findings indicate that AA release in intestinal cells may be caused by calcium-mediated phospholipase A2 activation or by products of microbial phospholipase C activity. They also suggest the further use of 14C-AA-labeled cells for studying agents and mechanisms that may influence the release of AA in the gastrointestinal tract.     

Effects of some antisecretory drugs on acid production, intracellular free Ca2+, and cyclic AMP production in isolated pig parietal cells

The effects of some inhibitors of acid secretion were tested on isolated, purified pig parietal cells. The cells were stimulated with 10(-4) M histamine, 10(-5) M carbachol, or 10(-7) M pentagastrin. The H,K-ATPase inhibitors SCH 28080 and omeprazole inhibited both the basal and secretagogue-stimulated acid production, as measured by aminopyrine accumulation, irrespective of the type of stimulator used. The IC50 value was 3-5 x 10(-9) M for SCH 28080 and 1-3 x 10(-8) M for omeprazole. Ranitidine inhibited the histamine-stimulated but not the basal acid production. The IC50 value was 2 x 10(-5) M. Stimulation of acid production with carbachol was blocked by pirenzepine, with an IC50 of 6 x 10(-7) M. Pirenzepine (10(-5) M) specifically blocked the carbachol-stimulated increase in cytosolic free Ca2+ in fura-2-loaded cells but not the increase in cytosolic free Ca2+ induced by histamine or pentagastrin. Ranitidine (10(-4) M) prevented the histamine-induced increase in Ca2+ and was also the only one of the four inhibitors which prevented the histamine-stimulated cAMP formation. SCH 28080 (10(-5) M) significantly potentiated the histamine-stimulated increase in cytosolic free Ca2+ and the formation of cAMP, whereas omeprazole (10(-5) M) was without effect.     

Effects of arachidonic acid metabolites and interleukin-1 on platelet activating factor production by hepatic sinusoidal endothelial cells from mice

The effects of interleukin-1 (IL-1) and arachidonic acid metabolites, prostaglandin (PG) E1, leukotriene (LT) B4 and LTC4, on the amount of platelet activating factor (PAF) produced and released by mouse hepatic sinusoidal endothelial cells were investigated. When hepatic sinusoidal endothelial cells were incubated with 1 microgram/mL of calcium ionophore (CaI) A23187, PAF production increased until 20 min after the start of incubation, but when the cells were incubated with PGE1 and CaI A23187, PAF production was significantly suppressed. On the other hand, when hepatic sinusoidal endothelial cells were incubated with IL-1 beta, LTB4 or LTC4 alone, PAF production significantly increased compared with that of the cells incubated without these substances. However, when the cells were incubated with PGE1 alone or with IL-1 beta, LTB4 or LTC4 and CaI A23187, these effects were not observed. These results indicated that PAF produced by hepatic sinusoidal endothelial cells is affected by IL-1 and arachidonic acid metabolites, suggesting that immune and inflammatory reactions in these cells may be regulated by chemical mediators produced by the cells themselves.     

Predominant generation of 15-lipoxygenase metabolites of arachidonic acid by epithelial cells from human trachea.

Epithelial cells of 99% purity and 92% viability were isolated from human tracheas obtained post mortem, and the cellular pathways for lipoxygenation of arachidonic acid were examined in vitro. The lipoxygenase metabolites were identified by comparison with synthetic standards during reversed-phase and straight-phase high-pressure liquid chromatography, UV spectroscopy, and gas chromatography/mass spectrometry. Epithelial cells incubated without arachidonic acid failed to generate detectable quantities of metabolites, while cells incubated with arachidonic acid at 1-50 micrograms/mf for 1-30 min invariably generated predominantly 15-lipoxygenase products, including 15-hydroxyicosatetraenoic acid (15-HETE), four isomers of 8,15-dihydroxyicosatetraenoic acid (two 8,15-diHETES and two 8,15-leukotrienes), at least one isomer of 14,15-dihydroxyicosatetraenoic acid, and smaller amounts of 12-HETE and 8-HETE, but little or no detectable 5-HETE or 5,12-diHETEs. The capacity of epithelial cells from human pulmonary airway to selectively generate 15-lipoxygenase metabolites of arachidonic acid suggests a potential role for the products as mediators of airway epithelial function.     

Study on adrenergic acid secretion using isolated parietal cells of guinea-pigs]

In order to investigate the effect of adrenergic nerve system on acid secretion at the cell-levels, acid secretion of isolated parietal cells stimulated by various adrenergic agonists was observed by measuring the accumulation of 14C-aminopyrine (A.P.). Both isoproterenol, beta receptor agonist, and salbutamol, beta-2 receptor selective agonist, increased A.P. accumulation, whereas dobutamine, beta-1 receptor selective agonist, showed no effect. And beta-2 receptor on parietal cells was detected by binding assay. These data may suggest that parietal cells have beta-2 receptors through which acid secretion will occur.     

Lipoxygenase metabolites of arachidonic acid modulate hematopoiesis

Lipoxygenase (LPO) metabolites of arachidonic acid participate in the activation and/or proliferation of a variety of cell types. In this study, we examined the role of LPO metabolites in controlling myelopoiesis and erythropoiesis in vitro. Monocyte depleted cells (MDC) prepared from human whole blood or whole mononuclear cells from human bone marrow were cultured in methylcellulose in the presence of various growth factors. Conditioned media containing human colony stimulating factors (CSF) or the tumor-promoting phorbol ester, phorbol myristate acetate (PMA), were added to induce myelopoiesis. Semipurified human erythropoietin (EPO) was added along with an endogenous source of burst- promoting activity (BPA) to induce erythropoiesis. The LPO inhibitor BW755C blocked all types of colony formation in a dose-dependent manner, with ID50 of 20 and 5 micrograms/mL for myeloid and erythroid colonies, respectively. MDC depleted of T cells were similarly inhibited by BW755C. Similar results were seen with two other LPO inhibitors, 1-phenyl-3-pyrazolidone and butylated hydroxyanisole. A fourth LPO inhibitor, nordihydroguaiaretic acid, inhibited at higher concentrations. Indomethacin, at concentrations that inhibit cyclooxygenase, had no significant effect, either alone or in combination with the LPO inhibitors. These results suggest that certain LPO products may be important mediators of both CSF- and PMA-induced myelopoiesis, and of BPA/EPO-induced erythropoiesis.     

Effect of amino acids on H+ production by isolated rat parietal cells

We investigated the hypothesis of a direct effect of amino acids on gastric parietal cells. [14C]aminopyrine uptake into isolated enriched rat parietal cells served as a quantitative index of H+ production. Cells were incubated in media containing 1 mM Ca2+ in the absence or presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX), or 3 mM Ca2+ without IBMX. Under these different conditions, L-arginine, L-phenylalanine and L-tryptophan (10(-6) M to 3 X 10(-2) M) failed to alter basal [14C]aminopyrine uptake as well as the response to submaximal stimulation by histamine, forskolin, N6O2-dibutyryladenosine-3',5'-(cyclic)-phosphate (db cAMP) or carbachol. Pentagastrin failed to elicit an appreciable response in the presence and absence of 10(-3) M of all three amino acids studied. It is concluded that in vivo the potent stimulation of gastric acid secretion by L-arginine, L-phenylalanine and L-tryptophan is mediated by other than direct mechanisms.     

Regulation of T-lymphopoiesis by arachidonic acid metabolites

The cloning efficiency of T-lymphocyte progenitor cells (CFU-T) is dependent on mononuclear cell concentration, with a triphasic growth curve. At low plating cell concentrations, hydrocortisone causes a dose-dependent decrease in cloning efficiency, whereas at high cell concentrations hydrocortisone causes increased cloning efficiency. To determine if the biphasic effects of hydrocortisone are through its inhibition of arachidonic acid metabolism, we tested the effects of various arachidonic acid metabolism inhibitors on cloning efficiency. Indomethacin, which inhibits cyclooxygenase, has no effect at low cell plating doses, but increases cloning efficiency at high cell doses. Prostaglandin E2 (PGE2) causes a dose-dependent inhibition of cloning efficiency at all cell doses. Caffeic acid, an inhibitor of lipoxygenase, causes a dose-dependent inhibition of CFU-T, particularly at lower cell concentrations. Leukotriene B4 (LTB4) restored caffeic acid-inhibited growth, as did addition of recombinant interleukins 1 and 2 (IL-1 and IL-2). These results support a regulatory role for arachidonic acid metabolites in T-lymphopoiesis. PGE2, a cyclooxygenase product, is inhibitory, whereas LTB4, a lipoxygenase product, is stimulatory through its role in IL-1 synthesis.     

Calcium-dependent signaling of acid secretion in isolated parietal cells from guinea pigs and its modification by ethanol]

Treatment of isolated parietal cells from guinea pig gastric mucosa with ethanol caused a rapid increase in [Ca2+]i and concomitant decrease in the capacity for carbachol-stimulated acid secretion in a dose dependent manner. Carbachol rapidly increased the [Ca2+]i from trimethoxybenzoic acid 8-(diethylamino)-octyl ester sensitive intracellular pool. In contrast, the increase with ethanol was through La3+ sensitive Ca2+ channel from external source, which suppressed the Ca2+ response subsequently stimulated with carbachol. Pretreatment of the cells with EGTA or La3+ completely prevented the elevation of [Ca2+]i with ethanol and preserved the Ca2+ response to carbachol. These findings indicate that ethanol-induced elevation of [Ca2+]i may desensitize the stimulation of carbachol. Furthermore, treatment of the parietal cells with ethanol increased the activity of protein kinase C in both cytosolic and membrane fractions of the cells. Activation of protein kinase C with phorbol diester suppressed the capacity for acid secretion. These results suggest that ethanol may inhibit the carbachol-stimulated acid secretion through the desensitization of Ca2+ response and the activation of protein kinase C.     

The effect of thrombin on the uptake and transformation of arachidonic acid by human platelets

Washed human platelets take up arachidonic acid from plasma and incorporate the fatty acid into the major classes of complex lipids. Thrombin impairs net incorporation. It activates endogenous phospholipases which liberate arachidonic acid from phospholipids. As a consequence of thrombin induced aggregation platelets release arachidonic acid intermediates formed by the action of platelet fatty acid cyclooxygenase and by platelet fatty acid lipoxygenase. Cyclooxygenase, but not lipoxygenase, is inhibited by aspirin and indomethicin. Analysis of the pathways of arachidonic acid metabolism may furnish new insight into platelet function and into disorders of primary hemostasis.     

Eoxins are proinflammatory arachidonic acid metabolites produced via the 15-lipoxygenase-1 pathway in human eosinophils and mast cells

Human eosinophils contain abundant amounts of 15-lipoxygenase (LO)-1. The biological role of 15-LO-1 in humans, however, is unclear. Incubation of eosinophils with arachidonic acid led to formation of a product with a UV absorbance maximum at 282 nm and shorter retention time than leukotriene (LT)C4 in reverse-phase HPLC. Analysis with positive-ion electrospray tandem MS identified this eosinophil metabolite as 14,15-LTC4. This metabolite could be metabolized to 14,15-LTD4 and 14,15-LTE4 in eosinophils. Because eosinophils are such an abundant source of these metabolites and to avoid confusion with 5-LO-derived LTs, we suggest the names eoxin (EX)C4, -D4, and -E4 instead of 14,15-LTC4, -D4, and -E4, respectively. Cord blood-derived mast cells and surgically removed nasal polyps from allergic subjects also produced EXC4. Incubation of eosinophils with arachidonic acid favored the production of EXC4, whereas challenge with calcium ionophore led to exclusive formation of LTC4. Eosinophils produced EXC4 after challenge with the proinflammatory agents LTC4, prostaglandin D2, and IL-5, demonstrating that EXC4 can be synthesized from the endogenous pool of arachidonic acid. EXs induced increased permeability of endothelial cell monolayer in vitro, indicating that EXs can modulate and enhance vascular permeability, a hallmark of inflammation. In this model system, EXs were 100 times more potent than histamine and almost as potent as LTC4 and LTD4. Taken together, this article describes the formation of proinflammatory EXs, in particular in human eosinophils but also in human mast cells and nasal polyps.     

Role of arachidonic acid metabolites in allergen-induced late responses

The sheep model of allergic airway disease shares many pathophysiological similarities with allergic airway disease in humans. Studies performed in this animal model present strong evidence that the release of arachidonic acid metabolites plays an important role in the development of late bronchial responses to antigen challenge. The release of leukotrienes through the lipoxygenase pathway during the acute bronchial obstruction after inhalation of Ascaris suum antigen represents the key factor for the initiation of the subsequent events, namely the late phase response and the bronchial hyperreactivity. If this hypothesis can be substantiated in patients with bronchial asthma then pharmacologic modification of the lipoxygenase pathway and/or products may be important in the treatment of asthma.