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PubMed1993

Unique pancreatic carcinoma cDNA found via subtracted libraries with limited normal tissue and tumor from the same patient.

We have approached the problem of isolating clones unique to specific malignancies such as T-cell acute lymphoblastic leukemia (ALL) and pancreatic adenocarcinoma by using subtractive hybridization techniques. Our initial studies involved using normal donor tissue (i.e., normal blood donors for ALL and cadaver renal transplant donors for normal pancreatic tissue) and cultured malignant cell lines. It occurred to us that normal pancreatic tissue from the same patient source as that of the malignant tissue might subtract out normal sequences more readily and enrich clones unique to pancreatic adenocarcinoma because of patient/donor identity. Using such a method meant that the amounts of tissue for overcoming this obstacle. We constructed independent UNI-ZAP-XR cDNA libraries (normal and malignant) and used them to amplify either the normal or malignant cDNA prior to subtractive hybridization. We then obtained rescued single stranded cDNA from the malignant ZAP library. The RNA which was not hybridized was isolated. The process was repeated and a double subtraction was effected. The residual non-hybridized RNA was used as a template for first and second strand synthesis. After the EcoRI adaptors were ligated to the double stranded cDNA it was cloned into Lambda ZAP II arms to form a double subtracted malignant cDNA library. A subtracted probe was prepared from the double subtracted cDNA library. Single stranded cDNA was rescued, double stranded plasmid was made, the plasmid DNA was digested with EcoRI, the digested DNA was run on a 1% SeaPlaque gel, and the insert cDNA was recovered using Ultra-Free MC and Ultra-Free Probind filters. The subtracted malignant cDNA library was probed with the subtracted probe and with normal cDNA (obtained from the normal ZAP library) and those plaques which were positive per the subtracted probe and negative per the normal cDNA were isolated; their cDNA inserts are being further characterized.

Actins↗

PubMed1996

HIV envelope-directed signaling aberrancies and cell death of CD4+ T cells in the absence of TCR co-stimulation.

HIV-1 infection in CD4(+) T cells initiates a viral cytopathic effect (CPE) that is dependent on the activation of intracellular protein tyrosine kinases (PTK). PTK in T cells are also activated during the course of TCR or CD4 receptor engagement and the manner of receptor engagement may generate signals leading either to cell proliferation, tolerance induction (anergy) or programmed cell death (PCD). We have identified PTK triggered during the interaction of cells stably expressing surface HIV envelope (gp 120/gp41; HIVenv) and CD4(+)T cells, which leads to extensive and rapid individual cell death. We have found that killing is accompanied by tyrosine phosphorylation and activation of the CD4-associated p56(ICK) kinase, and by activation of a second member of the scr family of PTK, p59(fyn) kinase, normally associated with T cell stimulation through the TCR. Interestingly, in contrast with normal T cell signaling, the zeta subunit of the TCR fails to become tyrosine-phosphorylated during signaling accompanying HIV-directed cell killing. Downstream activation of the ZAP-70 PTK also does not occur. Unlike T cell apoptosis triggered by soluble HIVenv glycoproteins, which requires co-stimulation of CD4 and the antigen-specific TCR, T cell killing by membrane-associated HIVenv does not require TCR co-stimulation, because aberrant signaling and cell death are triggered by CD4(+) but TCR- cell lines. These results are the first report where dual activation of the Lck and Fyn PTK does not result in normal downstream signaling through the ZAP PTK, We suggest by analogy to SCID resulting from ZAP-70 mutations, that the dissociation of upstream PTK activation from ZAP-70 signaling contributes to T cell depletion by HIV and to the development of AIDS.

Apoptosis↗

PubMedDate not supplied

Optimum pain relief with continuous epidural infusion of local anesthetics shortens the duration of zoster-associated pain.

OBJECTIVE: To investigate effects of continuous epidural infusion (CEI) of 0.5% bupivacaine added to intermittent epidural boluses (IEB) on the duration of zoster-associated pain (ZAP), as compared with continuous infusion of normal saline placebo added to IEB. DESIGN: A prospective, double-blind, randomized, placebo-controlled study. SETTING: A university hospital and an affiliated clinic in Japan from 1996 through 1999. PATIENTS: 56 immunocompetent herpes zoster (HZ) patients, 50 years or older, within 10 days of rash onset and with severe pain and eruption. INTERVENTIONS: Patients were hospitalized and randomly allocated into 2 groups. CEI group given CEI of 0.5% bupivacaine (0.5-1.0 mL/h) plus IEB of 0.5% bupivacaine 4 times daily (n = 29). IEB group given normal saline infusion plus IEB of 0.5% bupivacaine 4 times daily (n = 27). All patients received oral acyclovir 800 mg, 5 times daily, for 7 days. OUTCOME MEASURES: The number of days required for complete cessation of ZAP and the proportion of subjects with allodynia beyond 30 days. RESULTS: The median time to cessation of ZAP was significantly shorter in the CEI group than in the IEB group (29 days vs. 40 days, P = 0.002). The number of patients whose allodynia persisted beyond 30 days of treatment was significantly lower in the CEI group than in the IEB group (10% vs. 37%, P = 0.027). CONCLUSIONS: CEI of 0.5% bupivacaine plus IEB was associated with a shorter duration of ZAP and fewer patients with allodynia beyond 30 days, compared with IEB plus normal saline infusion. Patients at high risk for developing postherpetic neuralgia (PHN) can be managed with intensive therapies at the early stage of disease, such as CEI, which maintains effective analgesia and may reduce the burden of PHN.

Aged↗

PubMed1995

Kinetics, dose response, tachyphylaxis and cross-tachyphylaxis of vascular leakage induced by endotoxin, zymosan-activated plasma and platelet-activating factor in the horse.

Vascular leakage induced by intradermal injection of endotoxin, zymosan-activated plasma (ZAP) and platelet-activating factor (PAF) was measured in nine Thoroughbreds using 125-iodine human serum albumin (125I-HSA) as a marker in the blood. ZAP and PAF produced dose-dependent increases in vascular permeability with the maximum occurring within the first 15 min after injection. The vascular leakage induced by endotoxin was also dose-dependent, but the maximum occurred 2 h after intradermal injection. Intradermal sites previously injected with endotoxin were refractory to a second injection of endotoxin for up to 5 days. However, sites injected with endotoxin and re-injected with either ZAP or PAF remained responsive with increased vascular leakage compared to saline injected control sites re-injected with either ZAP or PAF. Diminished response to endotoxin challenge may contribute to the poor prognosis of endotoxaemia in the horse.

Animals↗

PubMed1987

Differences and similarities between human and rabbit neutrophil granulocyte responses in vitro: the effects of zymosan-activated plasma, phorbol myristate acetate and n-formyl-methionyl-leucyl-phenylalanine.

The amount of reactive oxygen intermediates (ROI) generated by activated polymorphonuclear neutrophils (PMN), as well as the closeness of contact between PMN and vessel wall, may determine whether PMN activators will induce the adult respiratory distress syndrome. We examined the ROI-generating and aggregating effects of zymosan activated plasma (ZAP), phorbol myristate acetate (PMA) and n-formyl-methionyl-leucyl-phenylalanine (FMLP), on isolated human and rabbit PMN. PMA, after a short lag phase, induced a large and long-lasting increase in ROI generation. The initial peak response was higher and more rapid in human than in rabbit cells. The reaction to FMLP occurred almost instantaneously, but was much weaker than that to PMA, and ROI generation returned to near baseline in less than 10 min. No species difference was seen. ZAP caused an FMLP-like ROI response in human cells, whereas no response was observed in rabbit PMN. PMN aggregation was induced by all three activators, most markedly by PMA. No species difference was detected for PMA; FMLP gave a stronger aggregation of rabbit than of human PMN, however, while the opposite was true for ZAP. In conclusion, ZAP was a potent stimulus for PMN aggregation, but had modest (or no) effects on the production of ROI. Marked differences between human and rabbit PMN responses were observed.

Animals↗

PubMed1993

Effect of dexamethasone on neutrophil accumulation and oedema formation in rabbit skin: an investigation of site of action.

1. The anti-inflammatory actions of dexamethasone on vascular and leukocyte responses in rabbit skin were investigated. 2. Neutrophil accumulation and oedema formation were simultaneously measured as the local accumulation of i.v. administered 111In-labelled neutrophils and 125I-labelled albumin. Systemically administered dexamethasone (3 mg kg-1) inhibited neutrophil accumulation induced by i.d. zymosan activated plasma (ZAP), N-formyl-methionyl-leucyl-phenylalanine (FMLP) and leukotriene B4 (LTB4) when co-injected with prostaglandin E2 (PGE2). Dexamethasone also inhibited oedema formation elicited by these stimuli and the responses induced by i.d. platelet activating factor (PAF)+PGE2 and bradykinin (BK)+PGE2. 3. Intradermal dexamethasone (2 x 10(-10) mol per site) but not indomethacin (10(-8) mol per site) inhibited oedema formation induced by i.d. ZAP+PGE2 and BK+PGE2. This inhibitory effect of dexamethasone was significant only with pretreatment periods of 4 h, shorter pretreatment periods resulting in greatly reduced effects. Intradermal dexamethasone had no effect on neutrophil accumulation induced by ZAP+PGE2. 4. Intradermal dexamethasone (2 x 10(-10) mol per site) had no effect on increase in blood flow induced by PGE2 as measured by 133Xenon clearance. 5. The accumulation of neutrophils isolated from donor rabbits pretreated with i.v. saline or dexamethasone (3 mg kg-1) was investigated in untreated recipient rabbits. The accumulation of neutrophils, induced by ZAP+PGE2, FMLP+PGE2 and LTB4+PGE2, from dexamethasone-pretreated donors was significantly smaller than the accumulation of neutrophils from saline-pretreated donors. 6. The results of this study suggest that dexamethasone can have a direct effect on vascular endothelial cells resulting in an inhibition of oedema formation. 7. Neutrophil accumulation can be inhibited by an effect of dexamethasone on the neutrophil itself or on the vascular endothelium. These results indicate that at least part of the inhibitory effect is on the circulating neutrophil induced by dexamethasone or a dexamethasone-induced product.

Animals↗

PubMed1993

E-type prostaglandins enhance local oedema formation and neutrophil accumulation but suppress eosinophil accumulation in guinea-pig skin.

1. Prostaglandins possess both pro- and anti-inflammatory actions depending on their route of administration and the experimental model used. In this study, we have investigated the effect of locally injected prostaglandins on oedema formation, neutrophil accumulation and eosinophil accumulation in inflammatory responses in guinea-pig skin. 2. Prostaglandin E1 (PGE1) significantly enhanced local oedema formation induced by zymosan-activated plasma (ZAP), bradykinin and in a passive cutaneous anaphylactic (PCA) reaction. The accumulation of ZAP-induced 111In-labelled neutrophils was also significantly enhanced by PGE1. In addition, the prostacyclin analogue, iloprost, enhanced ZAP-induced responses. 3. In contrast PGE1 decreased the accumulation of 111In-labelled eosinophils in skin sites. This was demonstrated on eosinophil accumulation and local oedema formation induced by PAF, compound 48/80 and in the PCA reaction. PGE2 also suppressed eosinophil accumulation while iloprost had no detectable effect. 4. Isoprenaline inhibited eosinophil accumulation in a dose-dependent manner with no effect on local oedema formation, except in the case of responses to ZAP where suppression was observed. 5. The vasodilator neuropeptide, calcitonin gene-related peptide (CGRP), enhanced local oedema formation but had no detectable effect on eosinophil accumulation. 6. In conclusion, the magnitude of a given response to an inflammatory mediator in vivo depends on the net effect of stimulation of several cell types e.g. arteriolar smooth muscle cells, microvascular endothelial cells, mast cells and accumulating leukocytes. In this study, we have demonstrated that different components of the inflammatory response in guinea-pig skin can be differentially modulated by E-type prostaglandins and isoprenaline, suggesting that cyclic AMP has an important regulatory role.

Alprostadil↗

PubMed1993

Role of prostaglandins and nitric oxide in acute inflammatory reactions in guinea-pig skin.

1. Oedema formation in skin is dependent on a synergism between mediators that increase vascular permeability and mediators that enhance local blood flow. Leukocyte accumulation is also enhanced by mediators that increase local blood flow. In this study, we have investigated whether nitric oxide (NO), an important endogenous vasodilator, could modulate oedema formation and leukocyte accumulation in guinea-pig skin. 2. Local administration of the NO synthesis inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), dose-dependently inhibited the oedema formation induced in response to intrademal injection of bradykinin or histamine. L-NAME, but not NG-nitro-D-arginine methyl ester (D-NAME); also inhibited oedema formation in response to i.d. injection of platelet-activating factor (PAF), zymosan-activated plasma (ZAP) and in a passive cutaneous anaphylactic (PCA) reaction. 3. N-iminoethyl-L-ornithine (L-NIO) was less effective and about 100 times less potent than L-NAME in inhibiting bradykinin-induced oedema formation. The cyclo-oxygenase inhibitor, ibuprofen, had little effect on oedema responses induced by bradykinin, PAF and in a PCA reaction. On the other hand, histamine-induced oedema formation was significantly suppressed by ibuprofen. 4. The inhibition by L-NAME of bradykinin-induced oedema formation was reversed by co-injection of sodium nitroprusside (SNP) or prostaglandin E1 (PGE1). 5. L-NAME inhibited 111In-eosinophil and 111In-neutrophil accumulation induced by i.d. injection of ZAP. 111In-eosinophil accumulation induced by PAF and in the PCA reaction was also inhibited by L-NAME but not by D-NAME. 6. Co-injection of SNP or PGE1, reversed the inhibition by L-NAME of ZAP-induced oedema formation and 111In-neutrophil accumulation. SNP, but not PGE1, also reversed the effects of L-NAME on ZAP-induced 111In-eosinophil accumulation.7. L-NAME caused a significant decrease in basal cutaneous blood flow when injected alone or with bradykinin. Again, SNP or PGE, reversed the effects of L-NAME suggesting that the inhibitory action of L-NAME on oedema formation and cell accumulation was due to an inhibition of vasodilator tone in the microcirculation.8. Thus, it appears that in guinea-pig skin the inhibition of the production of endogenous NO inhibits both leukocyte accumulation and oedema formation induced by different mediators of inflammation.Since administration of L-NAME also causes a local decrease in basal blood flow, we suggest that this is the mechanism by which it exerts anti-inflammatory effects in this model.

Acute Disease↗

PubMed1994

Role of adhesion glycoproteins CD18 and intercellular adhesion molecule-1 in complement-mediated reactions of rabbit skin.

1. The role of the adhesion glycoproteins CD18 and intercellular adhesion molecule-1 (ICAM-1) in inflammatory responses produced during a reversed passive Arthus (RPA) reaction and induced by zymosan and zymosan-activated plasma (ZAP) were studied in rabbit skin. 2. Oedema formation and haemorrhage were quantified by measuring accumulation of 125I-albumin and 111In-labelled red blood cells (111In-RBC) respectively. 3. Monoclonal antibody (mAb) R15.7 (anti-CD18), administered intravenously, abolished accumulation of 125I-albumin and 111In-RBC in dermal RPA reactions and in response to locally injected zymosan and ZAP. 4. When administered intravenously, the mAb RR1/1 (anti-ICAM-1) suppressed 125I-albumin and 111In-RBC accumulation in dermal RPA reactions and at sites treated with zymosan and ZAP. 5. Oedema formation in response to platelet-activating factor (PAF) and bradykinin (BK) either in the presence or absence of prostaglandin E2 (PGE2) were not affected by mAb R15.7 or by mAb RR1/1.1.1. 6. We conclude that oedema formation and haemorrhage associated with RPA reactions and in responses to zymosan and ZAP are completely CD18-dependent, and are mediated, at least in part, via ICAM-1. Responses to the neutrophil-independent oedema forming mediators, PAF and BK are not dependent upon CD18 or ICAM-1.

Animals↗

PubMed1991

Intravascular chemoattractants inhibit diapedesis by selective receptor occupancy.

An extravascular chemoattractant leads to migration of polymorphonuclear neutrophils (PMN) to that site, whereas intravascular administration leads to PMN oxidative activity and sequestration in microvessels but no diapedesis. This study examines the inhibitory role of intravascular chemoattractants. Rabbits (n = 37) were pretreated with zymosan-activated plasma (ZAP), leukotriene (LT) B4, or thromboxane (Tx) mimic. These agents were given intra-arterially, topically into plastic chambers taped atop sites of dermabrasion on the back, or into a lobar bronchus (n = 35). Intra-arterial injection of each chemoattractant resulted, 10 min later, in a 29-42% increase in intracellular PMN H2O2. In saline-infused animals, topical administration of the chemoattractants into dermabrasion chambers resulted in PMN accumulation per cubic millimeter after 3 h of 600 with ZAP, 536 with LTB4, and 643 with Tx mimic; all values higher than 46 with saline and 63 with normal plasma (all P less than 0.05). In other saline-infused animals, lobar lung aspiration of chemoattractants led to diapedesis as measured in bronchoalveolar lavage (BAL) fluid (PMN x 10(4)/ml) after 3 h: 19.0 with ZAP, 11.2 with LTB4 and 14.5 with Tx mimic, all greater than aspiration with saline or normal plasma 4.0 and 4.9, respectively (all P less than 0.05). Intra-arterial chemotactic administration inhibited subsequent PMN diapedesis in response to that same chemoattractant, both in dermabrasion chambers and in BAL fluid. When different intra- and extra-vascular chemoattractants were used diapedesis was promoted. Thus Tx infused intra-arterially and ZAP applied to a blister or lobar bronchus led to rapid cell migration and increased cell numbers.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1989

Neutrophil kinetics in rabbits during infusion of zymosan-activated plasma.

Complement activation in vivo produces neutropenia and pulmonary sequestration of neutrophils (PMNs) whereas in vitro activation increases PMN adherence and decreases PMN deformability. The present study examined PMN kinetics in vivo to determine if this sequestration was specific to the lung. Venous or arterial injections of radiolabeled PMNs were given to animals receiving infusions of zymosan-activated plasma (ZAP) or saline, and the PMN distribution was evaluated 10 min later. In control animals, the relative size of the marginated and circulating PMN pools was similar after venous or arterial injection and regional PMN retention increased as blood velocity slowed. ZAP infusion produced threefold increases in PMNs within pulmonary capillaries after venous injection and PMN retention was independent of blood velocity. After arterial injection, ZAP infusion produced PMN sequestration in all organs. Rigid (glutaraldehyde-fixed) PMNs injected into control rabbits showed increased lung recoveries similar to those of fresh PMNs injected into ZAP-treated rabbits. We conclude that activation of the complement system causes PMN sequestration in both the pulmonary and the systemic microvasculature and that the decrease in PMN deformability that occurs with activation of the PMN may be important in the genesis of PMN sequestration.

Animals↗

PubMed2006

Nitric oxide and prostaglandins potentiate the liver regeneration cascade.

The liver has the remarkable ability to regenerate following damage or surgical resection. Although this feature of the liver has been studied for over 100 years, the trigger of the liver regeneration cascade remains controversial. Recent experimental evidence supports the hypothesis that nitric oxide (NO) and prostaglandins (PGs), released secondary to an increase in the blood flow-to-liver mass ratio following two-thirds partial hepatectomy (PHx), work synergistically to trigger liver regeneration. To extend this research, the hypothesis that NO and PGs are potential therapeutic targets to potentiate the liver regeneration cascade is tested. The NO donor s-nitroso-n-acetylpenicillamine, the phosphodiesterase V antagonist zaprinast (ZAP) and PGI2 each potentiated c-fos messenger RNA expression, an index of initiation of the liver regeneration cascade, following PHx. Also, the triple combination of s-nitroso-n-acetylpenicillamine, ZAP and PGI2 potentiated c-fos messenger RNA expression. These results support the hypothesis that NO and PGs can potentiate initiation of the regeneration cascade. An additional index of liver weight restoration 48 h after PHx was also used to test the hypothesis, because this index encompasses the entire liver regeneration cascade. ZAP and 6-keto-PGF1alpha, a stable metabolite of PGI2, and the combination of ZAP and 6-keto-PGF1alpha, each potentiated liver weight restoration 48 h after PHx. These results also provide support for the hypothesis that NO and PGs are possible therapeutic targets to potentiate liver regeneration following surgical resection.

3',5'-Cyclic-GMP Phosphodiesterases↗

PubMed1991

Role of pulmonary inflammation in altered airway responsiveness in three sheep models of acute lung injury.

Pulmonary inflammation may contribute to increased airway responsiveness in experimental models of acute lung injury. Infusions of endotoxin, phorbol myristate acetate (PMA), or zymosan-activated plasma (ZAP) all result in the accumulation of polymorphonuclear leukocytes (PMNs) in the lung and alterations in lung mechanics. These three interventions have strikingly different effects on airway responses to aerosol histamine: ZAP does not increase airway responsiveness, whereas endotoxin causes a greater increase in airway responsiveness than does PMA. The present histologic study examines the question of whether the pattern and severity of PMN and mast cell accumulation in large- and medium-sized airways and lung periphery could contribute to the differences in airway responsiveness to histamine. Minimally instrumented sheep were given either an infusion of endotoxin (0.5 microgram/kg over 20 min), a bolus injection of PMA (5 micrograms/kg), or repetitive boluses of autologous ZAP (5 ml). Four and a half hours later, the animals were killed, and the left lung was removed and fixed in the distended state. Three levels of the left lung were examined by light microscopy: the large hilar bronchus, a medium-sized bronchus, and peripheral lung. The number of PMNs and mast cells in the airway wall were expressed as cells/mm length of airway circumference and in the lung periphery as cells/100 alveolar profiles. Both endotoxin and PMA caused a significant 2- to 3-fold increase in number of PMNs/mm of large airway circumference, the majority of PMNs being in the blood vessels of the lamina propria and submucosa; ZAP caused only minimal PMN accumulation in the blood vessels of the submucosa.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1982

Absence of inflammatory lung injury in rabbits challenged intravascularly with complement-derived chemotactic factors.

Systemic activation of the complement system results in the generation of chemotactic factors that have been suggested to play a role in the pathogenesis of inflammatory pulmonary diseases such as the adult respiratory distress syndrome. This led us to ask whether systemic complement activation by cobra venom factor (CVF) or intravascularly administered zymosan-activated rabbit plasma (ZAP) or rabbit C5a would result in lung injury. As had been described previously for CVF and ZAP, intravenously administered rabbit C5a also caused an acute neutropenia along with sequestration of neutrophils within the pulmonary vasculature. However, no significant lung inflammation as measured by neutrophil emigration or increased vascular permeability occurred with any of the three stimuli. Only when these agents were combined with anesthesia, surgical manipulation, and intubation did significant neutrophil emigration into alveoli occur, but again without any change in vascular permeability. After administration of ZAP, a decrease in dynamic compliance and an increase in pulmonary resistance as well as a transient period of hypoxemia occurred that was not observed after CVF or rabbit C5a treatment. Thus, our studies suggest that changes in lung function after ZAP instillation may not represent changes from complement activation alone in that they are not reproduced with CVF or rabbit C5a. We conclude that complement activation, as an isolated event, may be an insufficient insult in the lung to produce significant lung injury.

Airway Resistance↗

PubMed1985

Amphotericin B causes aggregation of neutrophils and enhances pulmonary leukostasis.

The influence of amphotericin B (AmB) on the aggregation of polymorphonuclear leukocytes (PMN) was examined by means of in vitro aggregometry as well as in an in vivo model of pulmonary leukostasis (PL). The AmB caused a dose-dependent aggregation of PMN that was partially blocked by addition of serum to the drug prior to its reaction with the PMN. No aggregation of PMN was seen after the addition of nystatin, a similar polyene antibiotic. In vivo studies were conducted in rabbits, where PL was induced by an intravenous infusion of zymosan-activated plasma (ZAP) or phorbol myristate acetate (PMA), and the degree of resulting leukostasis was expressed as the number of PMN per high power field (HPF). Animals in the control group had 6 +/- 3 PMN/HPF. This number increased to 12.4 +/- 5.6 when ZAP was infused and postmortem examination was performed 1 h later and to 17.4 +/- 4 if the examination was performed after 24 h. These numbers increased more than twice when AmB (1 mg/kg) was infused together with the ZAP. Increased PL after the infusion of ZAP and AmB was not attenuated by prior administration of methylprednisolone (30 mg/kg) to the animals. Infusions of AmB per se caused no significant PL but did cause increased pinocytosis in the pulmonary endothelium. Enhancement of PL by AmB was also examined in a model of PMA-induced PL.(ABSTRACT TRUNCATED AT 250 WORDS)

Amphotericin B↗

PubMed1992

The role of CD18-mediated adhesion in neutrophil sequestration induced by infusion of activated plasma in rabbits.

Infusion of activated plasma induces neutropenia and sequestration of neutrophils within the microvasculature. This study examined the role of the adhesion glycoprotein complex, CD11/CD18, in this sequestration. Rabbits pretreated with either the anti-CD18 monoclonal antibody (mAb) 60.3 or saline were given infusions of zymosan-activated plasma (ZAP) or saline. The effect of mAb 60.3 on the changes in circulating neutrophil counts, radiolabeled neutrophil kinetics in the lung, and the pulmonary microvascular accumulation of neutrophils induced by ZAP infusion was determined. The data show that pretreatment with mAb 60.3 did not inhibit either the rate of onset or the severity of the neutropenia but prevented the sustained neutropenia. In addition, mAb 60.3 completely prevented the ZAP-induced changes in radiolabeled neutrophil kinetics and largely inhibited the accumulation of neutrophils within the capillaries and the small vessels when evaluated after 15 min of ZAP infusion. We conclude that neutrophil accumulation is a two-step process, the first occurring through a CD18-independent mechanism that may involve a stimulus-induced decrease in neutrophil deformability and acts to slow neutrophil transit through the lung. The second step requires CD18-dependent adhesion and is needed for prolonged accumulation of neutrophils within the pulmonary microvasculature.

Animals↗

PubMed1999

Redundant role of the Syk protein tyrosine kinase in mouse NK cell differentiation.

Syk and ZAP-70 subserve nonredundant functions in B and T lymphopoiesis. In the absence of Syk, B cell development is blocked, while T cell development is arrested in the absence of ZAP-70. The receptors and the signaling molecules required for differentiation of NK cells are poorly characterized. Here we investigate the role of the Syk protein tyrosine kinase in NK cell differentiation. Hemopoietic chimeras were generated by reconstituting alymphoid (B-, T-, NK-) recombinase-activating gene-2 x common cytokine receptor gamma-chain double-mutant mice with Syk-/- fetal liver cells. The phenotypically mature Syk-/- NK cells that developed in this context were fully competent in natural cytotoxicity and in calibrating functional inhibitory receptors for MHC molecules. Syk-deficient NK cells demonstrated reduced levels of Ab-dependent cellular cytotoxicity. Nevertheless, Syk-/- NK cells could signal through NK1. 1 and 2B4 activating receptors and expressed ZAP-70 protein. We conclude that the Syk protein tyrosine kinase is not essential for murine NK cell development, and that compensatory signaling pathways (including those mediated through ZAP-70) may sustain most NK cell functions in the absence of Syk.

Animals↗

PubMed1988

Pulmonary effects of zymosan activated plasma and phorbol myristate acetate in anaesthetized and awake rabbits.

The ability of two polymorphonuclear granulocyte (PMN) activators, Zymosan activated plasma (ZAP) and Phorbol myristate acetate (PMA), to induce an adult respiratory distress syndrome (ARDS) type lung injury was compared in awake and anaesthetized rabbits. The preparatory procedure itself decreased the concentrations of circulating PMN and lymphocytes in anaesthetized animals. ZAP acutely lowered the number of circulating leukocytes due to a fall in PMN only, this was followed by a rebound. Both effects were more marked in awake than in anaesthetized animals. PMA caused a virtual disappearance of both PMN and lymphocytes from the blood. There was no rebound, and no difference between anaesthetized and awake animals. The activators caused equal increases in pulmonary arterial pressure (about 0.67 kPa) initially. This was followed by a return to baseline in ZAP animals, but a further increase in those given PMA. Increased airway pressure (0.4 kPa) was seen only in the PMA group; PaO2 decreased only in awake rabbits given PMA. Both activators, as well as the preparatory procedure itself, caused PMN accumulations in the alveolar septa, septal thickening, and modest perivascular edema with intact tissue architecture. PMA caused the most marked changes. Wet/dry lung weight ratios were only moderately increased. In conclusion, ZAP and PMA had different effects on circulating leukocytes, but gave nearly the same degree of PMN accumulation in the lungs. The modest edema indicated some increased microvascular leakage, but a fully developed ARDS-type lung injury did not occur.

Anesthesia↗