Role of platelet activating factor in development of thrombocytopenia and neutropenia in dogs with endotoxemia

OBJECTIVE: To determine the role of platelet activating factor (PAF) in lipopolysaccharide (LPS)-induced thrombocytopenia and neutropenia in dogs. ANIMALS: 42 dogs. PROCEDURES: Blood samples were obtained from dogs given LPS (40 microg/kg of body weight; n = 16), PAF (1 microg/kg; 6), PAF (5 microg/kg/h for 90 minutes; 4), or physiologic saline (0.9% NaCl) solution (0.1 ml/kg/h for 90 minutes; 3) IV to monitor changes in blood cell counts, using automated counters and blood smears stained with Giemsa. Blood samples were also obtained from dogs given LPS (40 microg/kg) that had (n = 5) or had not (6) been treated beforehand with TCV-309, a potent PAF antagonist. Concentration of PAF in blood was determined by use of 125I-radioimmunoassay in dogs given LPS at 1 mg/kg (n = 3) and 40 microg/kg (9). RESULTS: Thrombocytopenia and neutropenia were found in all dogs except those given saline solution. The LPS-induced thrombocytopenia was significantly suppressed by prior treatment with TCV-309. The PAF concentrations increased markedly 1 hour after injection of 1 mg/kg of LPS and increased slightly but significantly 10 minutes after injection of 40 microg/kg of LPS. CONCLUSION AND CLINICAL RELEVANCE: PAF plays an important role in the development of LPS-induced thrombocytopenia and neutropenia in dogs. Control of PAF production, PAF-induced effects, or both may be important in the treatment of dogs with gram-negative bacterial infections and associated thrombocytopenia and neutropenia.     

Influence of platelet activating factor on gastrointestinal electrical activity and some haematological and clinical parameters in the conscious miniature pig

The effects of intravenous (i.v.) infusion of platelet-activating factor (PAF), 100 ng/kg/min for 10 min, with and without pretreatment with a selective PAF-antagonist on gastrointestinal electrical activity, arterial pressure and clinical and haematological parameters were studied. Conscious miniature pigs with electrodes implanted in the wall of the antrum pylori and small and large intestine were used. Platelet-activating factor induced restlessness or depression, shivering, tachypnoea and coughing, retching and vomiting, hypotension and a delayed and sustained increase in leucocyte count with an increase in percentage of segmented neutrophils. The PAF-antagonist, SAH 63-675, administered at 10 mg/kg intravenously, inhibited these effects. Platelet-activating factor resulted in a decrease in electrical activity in the antrum and large intestine, whereas small intestinal activity was not significantly influenced. Pretreatment with the antagonist suppressed these inhibitory effects.     

Antagonism of endotoxin-induced disruption of equine gastrointestinal motility with the platelet-activating factor antagonist WEB 2086

The effect of pre-treatment with a selective platelet-activating factor (PAF) antagonist, WEB 2086, on the actions of low-dose endotoxin was evaluated in ponies prepared with gastrointestinal strain gauges. Endotoxin (0.1 microgram/kg i.v.) produced a marked reduction in gastric contraction amplitude and rate, and an increased frequency and reduced duration of jejunal phase III activity fronts (AFs). WEB 2086 (6.6 mg/kg) administered i.v. 10 min before the endotoxin, produced significant antagonism (P less than 0.001) of the effect of endotoxin on gastric contraction amplitude and rate. The combination of WEB 2086 and endotoxin produced gastric contractions of significantly (P less than 0.01) higher frequency than in the control studies. WEB 2086 also reduced endotoxin-induced abnormal phase III AFs in the jejunum and increases in heart rate and packed cell volume. These results provide evidence that endogenous PAF plays a role in mediating the acute effects of endotoxin on equine gastrointestinal motility.     

Roles of thromboxane A2 and 5-hydroxytryptamine in endotoxin-induced digital vasoconstriction in horses

OBJECTIVE: To evaluate the roles of 5-hydroxytryptamine (5-HT), thromboxane A2 (TxA2), and platelet-activating factor (PAF) in endotoxin-induced digital hypoperfusion in horses. ANIMALS: 6 healthy adult Thoroughbreds. PROCEDURES: Horses were treated with IV administration of saline (0.9% NaCl) solution (control treatment) or the 5-HT 1B/D selective antagonist, GR55562 (0.3 mg/kg), prior to tryptamine infusion (1.6 microg/kg/min for 30 minutes) to establish an effective GR55562 dose. In a crossover study, horses were treated with IV administration of saline solution (control treatment), aspirin (4 mg/kg, 2 hours or 4 days before lipopolysaccharide [LPS] infusion), GR55562 (0.3 mg/kg), the PAF antagonist WEB2086 (3 mg/kg), or aspirin plus GR55562 prior to LPS infusion (30 ng/kg for 30 minutes). Digital blood flow was measured by use of Doppler ultrasonography. Concomitant measurements of hoof wall and coronary band surface temperatures were made. Serial blood samples were collected and plasma 5-HT and TxA2 concentrations determined. RESULTS: GR55562 abolished tryptamine-induced digital hypoperfusion. Neither WEB2086 nor GR55562 affected LPS-induced alterations in digital perfusion or plasma mediator concentrations. Aspirin given 2 hours before LPS administration abolished the increase in plasma TxA2 concentration and significantly attenuated LPS-induced digital hypoperfusion. Aspirin given 4 days before LPS significantly attenuated the increase in plasma TxA2 concentration and digital hypothermia. Aspirin plus GR55562 had a greater effect on LPS-induced digital hypothermia than aspirin alone. CONCLUSIONS AND CLINICAL RELEVANCE: Thromboxane A2 and 5-HT played a role in mediating LPS-induced digital hypoperfusion in horses. Platelet-activating factor appeared unimportant in mediating LPS-induced 5-HT or TxA2 release or digital hypoperfusion.     

Evaluation of the effect of two dose rates of cyclosporine on the severity of perianal fistulae lesions and associated clinical signs in dogs

OBJECTIVE: To investigate the effect of cyclosporine (2 or 5 mg/kg every 24 hours) on perianal fistulae (PAF) lesions. STUDY DESIGN: Blinded randomized, prospective trial. ANIMALS: Dogs (n = 20) with perianal fistulae. METHODS: Dogs were randomly assigned to administration of either 2 mg/kg (n = 10) or 5 mg/kg (n=10) of cyclosporine orally every 24 hours for 8 weeks. Lesion surface area was measured, lesion severity was graded using a visual analog scale, and the presence and severity of clinical signs recorded every 2 weeks. RESULTS: Lesion variables were significantly reduced in both groups after 8 weeks and owners also reported a reduction in clinical sign severity. The 5 mg/kg dose rate significantly accelerated lesion resolution compared with 2 mg/kg. In the 2 mg/kg group, 20% of dogs had complete resolution of clinical signs and 10% had resolution of lesions. In the 5 mg/kg group, 40% of dogs had complete resolution of clinical signs and 60% had resolution of lesions. CONCLUSIONS: A dose rate of 5 mg/kg every 24 hours was more effective at reducing the surface area and severity of PAF lesions than 2 mg/kg every 24 hours but less effective at resolving PAF lesions than previous studies using dose rates > or =5 mg/kg every 12 hours. CLINICAL RELEVANCE: Cyclosporine at 5 mg/kg every 24 hours may be useful for the palliation of PAF lesions.     

Effects of WEB 2086, an antagonist to the receptor for platelet-activating factor (PAF), on PAF-induced responses in the horse.

Platelet-activating factor (PAF) causes oedema and neutrophil accumulation when injected into the skin of normal horses. PAF is also known to induce aggregation of horse platelets in vitro. The selective PAF receptor antagonist WEB 2086 has now been used to determine whether these effects are mediated by PAF receptor activation. Addition of WEB 2086 to equine platelets in vitro inhibited PAF-induced aggregation in a competitive reversible manner (pA2 = 7.14). Inhibition of in vivo inflammatory responses to PAF occurred after local administration of WEB 2086: wheal formation induced by 0.1 micrograms PAF/site was reduced by 1-10 micrograms WEB 2086/site. PAF (1 micrograms/site)-induced neutrophil accumulation was also inhibited by co-administration of 10 micrograms WEB 2086/site. Systemic administration of WEB 2086 (3 mg/kg iv) to 4 normal ponies inhibited PAF-induced wheal formation and ex vivo platelet aggregation. At 30 min after drug administration the concentration of PAF required to produce a half maximal aggregation response was increased 496 +/- 137 fold. At 6 h the degree of inhibition was markedly reduced and responses had returned to pre-treatment values by 24 h. PAF-induced increases in cutaneous vascular permeability were also reduced by 80% as early as 30 min after iv administration of WEB 2086 in these animals, the inhibition persisting for at least 6 h. These results suggest that in vitro and in vivo responses to PAF in the horse are mediated via activation to PAF receptors. WEB 2086 will therefore be a useful agent for studying the role of PAF in the pathogenesis of equine inflammatory conditions.     

The Effect of Intravenous Administration of Web 2086 on PAF-Induced Platelet Aggregation in Healthy Friesian Calves

The in vivo ability of the specific PAF-antagonist WEB 2086, a thienotriazolodiazepine, to inhibit platelet-activating factor (PAF) in cattle was investigated by in vitro determination of platelet aggregation curves. WEB 2086 was infused intravenously into a group of 5 healthy male Friesian calves in a dose of 3 mg/kg over 1 min. The resultant inhibition peaked between 30 min and 1 h after administration of WEB 2086. The inhibition was significantly reduced after 3 h and became non-significant after 6 h, but maximal pre-treatment aggregation had not been restored by 24 h after the injection of WEB 2086. These results confirm previous results obtained in vitro and suggest that WEB 2086 is a potent antagonist of PAF activity in calves. They also suggest that further clinical studies with WEB 2086 in cattle are desirable.     

Inflammatory effects of platelet activating factor (PAF) in equine skin.

Intradermal administration of PAF (0.001-1 micrograms/site), but not lyso-PAF (10 micrograms/site), in the horse caused an increase in cutaneous vascular permeability which was maximal by 32 min. Responses to PAF and histamine were reduced by coadministration of the histamine 1 receptor antagonist chlorpheniramine, although only the inhibition of histamine-induced responses was dose-related and statistically significant. The cyclo-oxygenase inhibitor indomethacin was without effect on PAF-induced increases in vascular permeability. These findings suggest that the actions of PAF on equine skin microvasculature may be partly due to histamine release but not to prostanoid formation. Coadministration of prostaglandin (PG) E2 enhanced the oedematous responses to both PAF and histamine, although PGE2 failed to exert direct permeability-increasing activity. In addition, and in contrast to PAF and histamine, PGE2 increased cutaneous blood flow and skin surface temperature. PAF, but not lyso-PAF, also caused neutrophil infiltration into the skin which was maximal at 2 h. No significant effects on eosinophil or mononuclear cell numbers were apparent up to 24 h after injection of PAF. These results are consistent with the concept that PAF may be a mediator of inflammatory disorders of the skin in the horse.     

Study on the Building Conditions of Acute Lung Injury in Mice

In order to explore the building conditions of acute lung injury, healthy Kunming mice were selected, by intraperitoneal injection of cascade dose of LPS (0, 2, 4, 6, 8, 10 mg/kg) to observe the mice respiratory frequency, mortality, lung W/D value and the changes of tissue structure in different conditions, and detect the expression changes of inflammation cytokine, IL-10,TNF-α, IL-1β and IFN-γ. The results showed that compared with control group, lung W/D value in 4 mg/kg LPS group significantly increased (P<0.05) and lung W/D values in 6, 8 and 10 mg/kg LPS groups extremely significantly increased (P<0.01). Pathological analysis showed that 6 mg/kg LPS group appeared lung congestion, alveolar luminal and pulmonary interstitial exudation, alveolar septal thickening, and a small amount of neutrophil infiltration. 8 and 10 mg/kg LPS groups appeared pulmonary congestion, alveolar and pulmonary interstitial exudation, alveolar septal thickening and neutrophil infiltration. Compared with control group, collagen fibers of the lung tissue in 6, 8, 10 mg/kg LPS group increased, and more appeared in the lung around the trachea, 10 mg/kg LPS group was the most obvious. The inflammatory factors in 2, 4, 6, 8 and 10 mg/kg LPS groups had extremely significantly increased compared with control group (P<0.01). Pathological biopsy and related indicators showed that the model of mice could be successfully constructed by intraperitoneal injection of 8 mg/kg LPS for 12 h.     

小鼠急性肺损伤造模条件的探究

为探究构建急性肺损伤模型的条件,本试验选用健康昆明小鼠,经腹腔注射递增剂量脂多糖（LPS）（0、2、4、6、8、10 mg/kg）,观察不同条件下小鼠呼吸频率、死亡率、肺脏干湿重比值及组织结构变化,检测炎症因子IL-10、TNF-α、IL-1β及IFN-γ在不同程度肺损伤中的表达量变化。结果显示,4 mg/kg LPS组肺脏干湿重比值显著高于对照组（P<0.05）;6、8和10 m/kg LPS组肺脏干湿重比值极显著高于对照组（P<0.01）。病理切片分析显示,6 mg/kg LPS组小鼠肺脏出现充血,肺泡腔及肺间质出现渗出,肺泡隔增厚,出现少量中性粒细胞浸润;8、10 mg/kg LPS组小鼠肺脏充血明显,肺泡腔及肺间质出现渗出,肺泡明显隔增厚,出现中性粒细胞浸润;与对照组相比,6、8、10 mg/kg LPS组肺组织中胶原纤维大量增多,且多出现在肺气管周围,10 mg/kg LPS组现象最明显。炎症因子检测分析结果显示,与对照组相比,2、4、6、8、10 mg/kg LPS组炎症因子均极显著增加（P<0.01）。结合病理组织切片及相关检测指标表明,昆明小鼠腹腔注射8 mg/kg LPS并作用12 h,可成功构建急性肺损伤模型。     

A comparison of the actions of platelet activating factor (PAF) antagonists WEB 2170 and WEB 2086 in the horse

Foster, A.P., Cunningham, F.M., Andrews, M.J., Lees, P. A comparison of platelet activating factor (PAF) antagonists WEB 2170 and WEB 2086 in the horse. J. vet. Pharmacol. Therap. 16, 477–487.
The effects of the selective platelet activating factor (PAF) receptor antagonist WEB 2170 on PAF-induced responses in equine cells and tissues have been examined and compared with those of WEB 2086. In initial experiments WEB 2170 was shown to inhibit in vitro platelet aggregation in a dose-dependent, competitive reversible manner (pA₂= 7.21). Co-administration of the antagonists with either PAF or histamine also inhibited PAF, but not histamine, induced wheal formation and PAF-induced neutrophil accumulation in vivo in equine skin. Intravenous (i.v.) administration of both drugs at a dose of 0.1 mg/kg blocked PAF-induced ex vivo platelet aggregation. The inhibition produced by WEB 2170 was greater and, at 30 min, this drug also reduced the slope and maximal response. Wheal formation in the skin was significantly inhibited for up to 6 h by WEB 2170 administered i.v., the reduction being more prolonged than that obtained with WEB 2086. Neutrophil accumulation in the skin was also significantly reduced for up to 24 h by WEB 2170, whilst no significant inhibition was produced by WEB 2086. These results demonstrate that WEB 2170, like WEB 2086, is an effective antagonist of PAF in the horse. Moreover, when given i.v., WEB 2170 appears to be a more potent PAF inhibitor than WEB 2086.     

Effects of dietary supplementation with fish oil on in vivo production of inflammatory mediators in clinically normal dogs

OBJECTIVE: To evaluate the effect of diets enriched with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on in vivo production of interleukin (IL)-1, IL-6, tumor necrosis factor (TNF)-alpha, prostaglandin E2 (PGE2), and platelet-activating factor (PAF) in dogs. ANIMALS: 15 young healthy dogs. PROCEDURES: Dogs were randomly allocated to receive an isocaloric ration supplemented with sunflower oil (n=5), fish oil (5), or fish oil plus vitamin E (5) for 12 weeks. At week 12, in vivo production of inflammatory mediators was evaluated in serum at multiple time points for 6 hours following stimulation with IV administration of lipopolysaccharide (LPS). RESULTS: Serum activity or concentration (area under the curve) of IL-1, IL-6, and PGE2 significantly increased after LPS injection in all groups but to a lesser extent in dogs receiving the fish oil diet, compared with results for dogs receiving the sunflower oil diet. Serum activity of TNF-alpha and PAF concentration also increased significantly after LPS injection in all groups but did not differ significantly among groups. CONCLUSIONS AND CLINICAL RELEVANCE: A fish oil-enriched diet consisting of 1.75 g of EPA/kg of diet and 2.2 g of DHA/kg of diet (dry-matter basis) with an n-6:n-3 fatty acid ratio of 3.4:1 was associated with significant reductions in serum PGE2 concentrations and IL-1 and IL-6 activities. Results supported the use of EPA- and DHA-enriched diets as part of antiinflammatory treatments for dogs with chronic inflammatory diseases. Additional studies in affected dogs are warranted to further evaluate beneficial anti-inflammatory effects of EPA- and DHA-enriched diets.     

复合植物精油对脂多糖刺激仔猪肝脏的保护作用

试验旨在研究复合植物精油(OCT)对脂多糖(LPS)刺激仔猪肝脏的保护作用。选取18头仔猪,随机分为对照组、LPS组和OCT+LPS组,每组6个重复。对照组与LPS组饲喂基础日粮,OCT+LPS组在基础日粮中添加50 mg/kg OCT。试验期21 d。于试验第21天,LPS组与OCT+LPS组仔猪腹腔注射LPS,对照组注射等量的生理盐水,3 h后采血,6 h后屠宰。结果表明:与对照组相比,LPS刺激提高了血浆谷丙转氨酶(ALT)、谷草转氨酶(AST)、碱性磷酸酶(ALP)、谷酰转肽酶(GGT)、肝脏诱导型一氧化氮合酶(i-NOS)的活力(P0.05),肝脏热休克蛋白70(HSP70)基因的相对表达量显著提高(P0.05);仔猪肝脏表皮生长因子(EGF)、白细胞介素10(IL-10)、胰岛素样因子(IGF-1)、丝氨酸蛋白激酶(mTOR)基因的相对表达量显著降低(P0.05)。在日粮中添加50 mg/kg的OCT,可缓解LPS导致的仔猪血浆ALT、AST、GGT活力的升高以及肝脏i-NOS活力的升高(P0.05),且有缓解LPS导致的仔猪肝脏MPO活力升高的趋势(P0.1),另外可缓解LPS导致的仔猪肝脏HSP70基因相对表达量的升高以及EGF、IL-10、IGF-1、mTOR等基因相对表达量的降低(P0.05)。综上可知,日粮中添加50 mg/kg的OCT可缓解LPS刺激引起的肝脏炎症反应,提高仔猪肝脏细胞的生长和增殖,进而缓解LPS刺激导致的仔猪肝脏氧化应激损伤。     

Effect of Platelet-Activating Factor Antagonist L-691,880 on Low-Flow Ischemia-Reperfusion Injury of the Large Colon in Horses

Objective—To determine the effect of platelet-activating factor (PAF) antagonist L-691,880 on low-flow ischemia and reperfusion (I-R) of the large colon in horses. Animals —12 adult horses. Experimental Design—Horses were anesthetized, and the large colon was exteriorized through a ventral median celiotomy and instrumented. Colonic arterial blood flow was reduced to 20% of baseline (BL) and maintained for 3 hours; flow was then restored, and the colon was reperfused for 3 hours. One of two solutions was administered intravenously 30 minutes before reperfusion: group 1, 10 mL/kg 0.9% NaCl; and group 2, 5 mg/kg PAF antagonist L-691,880 in 0.9% NaCl. Hemodynamic variables were monitored and recorded at 30-minute intervals. Systemic arterial and colonic venous blood were collected for measurement of blood gas tensions, oximetry analyses, packed cell volume, and total plasma protein concentrations. Colonic venous blood was collected for determination of lactate, 6-keto prostaglandin F_1α (6-kPG), prostaglandin E₂ (PGE₂), and thromboxane B₂ (TXB₂) concentrations. Full-thickness biopsy specimens were harvested from the left ventral colon for histological evaluation. Results—There were no significant differences between the two groups for any hemodynamic or metabolic variables. Colonic venous pH decreased, and carbon dioxide tension and lactate concentration increased during ischemia but returned to BL values during reperfusion. Colonic venous 6-kPG concentration was significantly increased above BL value at 2 hours and remained increased through 6 hours in horses of both groups. Colonic venous PGE₂ concentration was significantly greater in group 2 compared with group 1 throughout the study. Colonic venous PGE₂ concentration was increased above BL value from 3 to 6 hours in horses of both groups. Colonic venous TXB₂ concentration was not different between groups but was significantly increased above the BL value for the first hour of reperfusion. Low-flow I-R of the large colon caused significant mucosal necrosis, hemorrhage, edema, and neutrophil infiltration; however, there were no differences in histological variables between vehicle-control and PAF antagonist-treated horses. Conclusion—No protective effects of PAF antagonist L-691,880 were observed on colonic mucosa associated with low-flow I-R. Additionally, deleterious drug-induced effects on hemodynamic and metabolic variables and colonic mucosal injury were not observed.     

Platelet activating factor is a mediator of equine neutrophil and eosinophil migration in vitro.

Platelet activating factor (PAF) is known to be a chemoattractant for equine neutrophils in vivo and in vitro. In this study the in vitro migratory response of equine eosinophils and neutrophils to PAF has been examined and compared with that to leukotriene (LT)B4. PAF (10(-8) to 10(-5) M), but not lyso-PAF (10(-6) M), caused dose related migration of both equine eosinophils and neutrophils, maximal responses occurring at 10(-6) M. Responses to PAF were inhibited by the receptor antagonist WEB 2086. LTB4 (10(-8) to 10(-6) M) also induced migration of both cell types, although the maximum effect was observed with a 10-fold lower concentration. Moreover, the maximum response of equine eosinophils to LTB4 was significantly greater than to PAF. It is concluded that LTB4 and PAF, if released in vivo at sites of allergic or inflammatory reactions, could mediate the recruitment of leucocytes to the involved tissue.     

A study of the effect of a platelet activating factor (PAF) receptor antagonist on antigen challenge of horses with chronic obstructive pulmonary disease

Antigen challenge involving exposure to straw and mouldy hay for 7 h produced lung function changes and neutrophil recruitment to the lungs in horses with chronic obstructive pulmonary disease (COPD). During the challenge, an increase in radiolabelled neutrophils in the lungs occurred, together with increased respiratory rate and pleural pressure. The role of platelet activating factor (PAF) in antigen-induced neutrophil accumulation, and increased pleural pressure and respiratory rate was investigated by administering the PAF receptor antagonist WEB 2086 to asymptomatic COPD horses prior to antigen challenge. WEB 2086 (3 mg/kg i.v.) did not affect antigen-induced changes in either neutrophil accumulation or respiratory function. These results suggest that PAF may not be an important mediator of the response to antigen in equine COPD.     

Endotoxin in the conscious piglet: Its effects on some general and gastrointestinal myoelectrical parameters

The effect of an intravenous bolus injection of endotoxin, 0.1, 1 or 10 g/kg, on rectal temperature, clinical appearance, haematological parameters, and on gastrointestinal electrical activity was examined in 11 conscious piglets of 4–5 weeks of age, with implanted electrodes in the antrum pylori, duodenum, jejunum and ileum. All doses resulted in a significant and dose-dependent increase in rectal temperature, in pronounced clinical signs and in distinct changes in haematological values. These included shivering, depression, respiratory distress, a leukopenia (0.1 g/kg) or a leukocytosis (1 g/kg) with a shift to the left, an accelerated sedimentation rate and a decreased packed cell volume. Doses of 1 and 10 g/kg induced a transient inhibition of gastroduodenal electrical activity. These results suggest that, in the piglet, endotoxin primarily manifests general clinical signs and that the gastrointestinal effects coincide with these.     

Changes in plasma alpha 1-acid glycoprotein concentration and selected immune response in broiler chickens injected with Escherichia coli lipopolysaccharide

1. Changes in plasma alpha1-acid glycoprotein (AGP) concentration and immune responses following Escherichia coli lipopolysaccharide (LPS) injection were studied in broiler chickens. 2. Higher plasma AGP concentrations were observed from 12 to 48 h after a single injection of LPS. 3. The highest concentration of plasma AGP was observed on day 2 followed by a gradual decrease in chicks injected with 150 mug/kg body weight of LPS every day for 13 d. 4. Plasma AGP concentration in chicks injected daily with LPS at 900 mug/kg body weight for 13 d increased on day 2, and decreased on day 4 to the concentration found before the injection. The concentration increased again on day 10. 5. Changes in plasma interleukin-1 (IL-1) like activity were similar to those in plasma AGP concentration when LPS was injected daily at 900 mug/kg body weight for 3 d. 6. Responses of blood mononuclear cell (MNC) proliferation to mitogen or concanavalin A, (Con A), and pokeweed mitogen (PWM) were positively correlated with changes in plasma AGP concentration. 7. The results suggest that plasma AGP concentration could be used as a positive indicator of changes in blood MNC proliferation to a mitogen and in plasma IL-1 like activity.     

The impact of acute phase response on the plasma clearance of antipyrine, theophylline, phenytoin and nifedipine in rabbits

The impact of acute phase response (APR) on the plasma clearances of antipyrine, theophylline, phenytoin and nifedipine was studied using 50 female rabbits. APR was induced by a bolus intramuscular injection of Escherichia coli lipopolysaccharide (LPS, 50 microg/kg). No abnormal findings, other than an increase in rectal body temperature and the plasma concentration of interleukin-6 (IL-6), were observed in the LPS-treated animals. Twenty-four hours after LPS injection, the pharmacokinetic parameters of the four drugs were obtained following intravenous administrations of antipyrine (7 mg/kg), theophylline (5 mg/kg), phenytoin (10 mg/kg) and nifedipine (1 mg/kg). Total body clearances of antipyrine, theophylline, phenytoin and nifedipine in LPS-treated rabbits decreased, and terminal elimination half-life and the mean residence time of these drugs increased compared with those in the control rabbits. The apparent volume of distribution for phenytoin and nifedipine increased after the LPS injection, although the binding percentage of the drugs with plasma protein did not change. These results suggested that APR appears to decrease the plasma clearances of these drugs in rabbits, which may be due to the suppression of the activity of cytochrome P450 enzymes.     

Synergistic action of E. coli endotoxin and Pasteurella multocida type A for the induction of bronchopneumonia in pigs

This study aimed to investigate whether Escherichia coli endotoxin (LPS) may predispose the lung to an infection with Pasteurella multocida type A (Pma) and to determine the LPS concentration needed to reproduce clinical signs of bronchopneumonia. Twenty-four hours before inoculating Pma or sterile growth medium, piglets were tracheally instilled with 10, 100 or 400 microg/kg LPS. Cough, body temperature, daily weight gain (DWG) bronchoalveolar lavage fluid (BALF) cells and volume of pneumonic lung were measured. Changes in breathing pattern (Penh) were assessed by whole body barometric plethysmography. No significant changes were observed in Pma-treated or in control animals. Each LPS doses induced DWG reduction while the higher generated a severe subacute interstitial pneumonia causing hyperthermia and an increase in Penh. The combination of the lower LPS doses with Pma produced an asymptomatic bronchopneumonia leading to DWG reduction, rise in Penh and an increase in BALF macrophages and neutrophils. With 400 microg/kg LPS, Pma worsened the inflammatory process as illustrated by cough, hyperthermia, major DWG reduction and by a greater Penh response. Lung lesions consisted of severe exudative bronchopneumonia. We concluded that LPS may negatively influence growth, predispose to persisting lung inflammatory process and promote Pma infection depending on the dose previously administered.