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Biomedical subjects

M Sielczak

Publications and source records attributed to M Sielczak.

At least 19 recordsLinked to original sources
PubMed1997

Effects of the 5-lipoxygenase inhibitor A-64077 on intestinal hypothermic organ preservation injury.

The effects of the orally active selective 5-lipoxygenase inhibitor Zileuton (A-64077, (N-1(1-benzo{b}thien-2-ylethyl)-N-hydroxyurea) were studied in a canine model of hypothermic intestinal organ ischemia-reperfusion (I/R) injury (transplant preservation injury). Forty-eighty hours of hypothermic intestinal ischemia utilizing Collin's flush, followed by 1 hr of reperfusion (transplantation) in A-64077-treated animals, resulted in a 3-fold increase in intestinal oxygen uptake and blood flow relative to the untreated controls. The postreperfusion movement of fluid from the microcirculation into the intestinal lumen significantly increased in the control animals at reperfusion, and A-64077 treatment dramatically exacerbated this phenomenon. Mucosal neutrophil infiltration, or the processes leading to infiltration, significantly increased after 48 hr of cold ischemia and 1 hr of normothermic reperfusion in the untreated animals. A similar response was observed in A-64077-treated dogs, but the absolute levels of MPO were 10-fold less relative to untreated animals, including intestinal tissue obtained before I/R. Hypothermic I/R injury in this model resulted in severe histologic injury. A-64077-treated dogs, however, demonstrated significant improvements in histologic injury. Mucosal synthesis of LTB4 rose significantly after cold I/R injury and was abrogated by A-64077 treatment. The synthesis of PGE2 significantly increased after cold I/R in both untreated and A-64077-treated dogs. The increase in PGE2 production after hypothermic I/R in the A-64077-treated animals was higher relative to the untreated control animals. In conclusion, this study indicates that arachidonic acid metabolism via the 5-lipoxygenase pathway plays a significant role in the pathophysiology of hypothermic intestinal I/R injury. Furthermore, the 5-lipoxygenase inhibitor A-64077 possesses favorable pharmacologic and biologic responses in this intestinal injury and should be considered in the clinical amelioration of intestinal transplantation preservation injury.

Animals↗
PubMed1996

Effect of TYB-2285 on antigen-induced airway responses in sheep.

We studied the effect of a new antiallergic compound, TYB-2285 (3,5-bis(acetoxyacetylamino)-4-chlorobenzonitrile), on antigen-induced early and late bronchoconstriction and airway responsiveness in conscious allergic sheep. The same general protocol was used for all studies, except that the dosage and time of TYB-2285 treatment was varied. The basic protocol consisted of determining airway responsiveness to inhaled carbachol, then measuring the airway responses to Ascaris suum antigen challenge followed 1 day later by a post challenge assessment of airway responsiveness. Specific lung resistance (SRL) was used to measure the airway responses to antigen and carbachol and the concentration of carbachol that caused a 400% increase in SRL (PC400) was used as a measure of airway responsiveness. All protocols were of crossover design, such that each sheep served as its own control and each protocol employed six to eight animals. In all instances, TYB-2285 or vehicle control (methylcellulose) was given orally. When TYB-2285 (100 mg/kg) was given at 16 and 2 h before the challenge, the early response, the late response and the post antigen-induced airway hyperresponsiveness (AHR) as indicated by a decrease in the PC400 was inhibited significantly. TYB-2285 (100 mg/kg), when given 1 h after challenge, inhibited the late response and AHR significantly. TYB-2285 (100 mg/kg), when given 8 h after the challenge, also inhibited the antigen-induced AHR. When animals were given TYB-2285 (100 mg/kg) at 32, 56 and 80 h after the challenge, the antigen-induced AHR that persisted (for 1 week) in the control trial was reversed to the normal level. TYB-2285 (30 mg/kg), when given at 1, 32, 56 and 80 h after the challenge, inhibited late response slightly and reversed the persistent AHR to the normal level. At lower doses (3 and 10 mg/kg) there was no protection of the early response, the late response or AHR. Pretreatment with TYB-2285 (100 mg/kg) also prevented the antigen-induced influx of eosinophils in bronchoalveolar lavage obtained 24 h after segmental antigen challenge. TYB-2285 did not inhibit histamine or LTD4-induced bronchoconstriction nor did the active metabolites of TYB-2285, TC-286 and TC-326 inhibit acetylcholine-induced contraction of sheep tracheal smooth muscle. These results suggest that TYB-2285 has both antiallergic and antiinflammatory properties in the sheep model of allergic bronchoconstriction. The compound demonstrates both prophylactic and therapeutic activity and, therefore, may be potentially useful in the treatment of allergen-induced airway disease.

Animals↗
PubMed1993

The effects of a cysteinyl leukotriene antagonist (ONO-1078) on antigen-induced responses in allergic sheep.

The cysteinyl leukotrienes (LTC4/D4/E4) are putative mediators of asthma. In this study we used sheep allergic to Ascaris suum antigen to examine the effects of a novel orally active cysteinyl LT antagonist, ONO-1078, on antigen-induced early and late responses, airway inflammation, post challenge (24 h) airway hyperresponsiveness (AHR) and mucociliary clearance. Airway responses to antigen were determined by measuring specific lung resistance (SRL) before and for 8 h after challenge, bronchoalveolar lavage (BAL) was used to estimate airway inflammation, and airway responsiveness was measured by determining the carbachol dose that increased SRL by 400% (PC400). We also used a radiographic technique to measure the antigen-induced change in tracheal mucus velocity (TMV), a marker of mucociliary clearance. In two trials separated by at least 21 days, sheep were treated once with ONO-1078 (30 mg/kg, p.o.) and once with placebo (0.5% methylcellulose), 2 h before and 4 h after antigen challenge. Treatment with ONO-1078 (n = 7) provided 40% protection (p < 0.10) against the peak early increase in SRL, resulted in a more rapid reversal of the early response, and provided 96% protection against the peak late (6-8 h) increase in SRL. ONO-1078 also inhibited the AHR 24 h after challenge. In the drug trial, PC400 was unchanged as compared to pre-challenge, whereas in the placebo trial, PC400 was decreased 1.4-fold (p < 0.05). Treatment however, did not affect BAL cell numbers or differential.(ABSTRACT TRUNCATED AT 250 WORDS)

Airway Resistance↗
PubMed1991

Separation of late bronchial responses from airway hyperresponsiveness in allergic sheep.

Allergic sheep with antigen-induced early and late responses were used to determine whether airway hyperresponsiveness (AHR) to carbachol is present during the late response and whether blocking the late response with the leukotriene D4 (LTD4) antagonist MK-571 also blocks this AHR. To do this, we first showed that MK-571 blocked the antigen-induced late response, and then, in a separate study, we determined the effect of MK-571 treatment on airway responsiveness 6 h after antigen challenge (at the start of the late response). MK-571 (5 mg, by metered dose inhaler) given 30 min before and 4 h after Ascaris suum challenge had no effect on the acute response to antigen but blocked (P less than 0.05) the late response compared with placebo (n = 7). In the second study (n = 6), the antigen-induced acute increases in mean specific lung resistance (sRL) were also similar in the placebo (249%) and drug trials (247%). By 6 h postchallenge, however, mean sRL in the placebo trial began to increase (54%, P less than 0.05), whereas in the drug trial mean sRL was baseline. Nevertheless, AHR was apparent in both trials as indicated by a mean twofold leftward shift in the dose-response curves to inhaled carbachol (P less than 0.05 vs. prechallenge). Bronchoalveolar lavage at 6 h showed that MK-571 did not prevent the inflammatory cell influx into the lung. These observations suggest that although LTD4 may be a mediator of the late response in sheep, it is not a primary mediator affecting cholinergic AHR during this period.

Airway Resistance↗
PubMed1990

A bradykinin-antagonist blocks antigen-induced airway hyperresponsiveness and inflammation in sheep.

The effects of a new bradykinin-antagonist, NPC-567 (D-Arg [hydroxyproline3, D-phenylalanine7] bradykinin) were studied on antigen-induced airway hyperresponsiveness and inflammation in allergic sheep (n = 7). Specific lung resistance (sRL) was used to assess airway responses to inhaled Ascaris suum-antigen. Airway responsiveness was determined from slopes of cumulative dose-response-curves (DRC) to inhaled carbachol. DRCs were performed at baseline and 2 h after an inhalation challenge with antigen. Bronchoalveolar lavage, performed before antigen-challenge and after the post-challenge DRC was used to assess antigen-induced inflammatory changes. For these studies NPC-567 was given as an aerosol (20 breaths, 10 mg/ml) 30 min before antigen challenge and (400 breaths, 2 mg/ml) co-administered with the Ascaris suum antigen. The immediate increase in specific lung resistance (sRL) after antigen challenge was not different with (232 +/- 152% increase) or without drug pre-treatment (148 +/- 129% increase). In the control trial, antigen challenge led to an increase in slope of the post-challenge DRC by 123 +/- 118% compared to baseline (p less than 0.05). This hyperresponsiveness was almost completely prevented by NPC-567 (increase in slope 32 +/- 64%, p less than 0.05 vs. control). Similarly, the antigen-induced inflammatory response, characterized by a significant 3.3-fold increase over baseline in the percentage of neutrophils in the control-experiment, was blocked by the bradykinin-antagonist. These results suggest that bradykinin may be involved in the pathogenesis of antigen-induced airway inflammation and the consequent development of airway hyperresponsiveness in sheep.

Administration, Inhalation↗
PubMed1987

Laser smoke effect on the bronchial system.

The photoresection of endobronchial tumors produces smoke which is partly inhaled by the patient as well as the surgical staff. In an animal study we investigated whether a single exposure or repetitive exposures to smoke might have harmful side effects on the airways. Eleven sheep were exposed to smoke produced by laser-vaporizing (6,500 J) sections of bronchial tissue (1 cm3) in a Plexiglas chamber. The smoke analysis revealed 0.92 mg/liter particles with a mean particle size of 0.54 micron. Carbon monoxide content was estimated as 0.04%. We measured the effects of one or three separate ten-minute exposures on airway resistance, gas exchange, and mucociliary clearance rate in the trachea. We found that the smoke inhalation resulted in a decrease of arterial PO2 with relatively little change in airway mechanics. Tracheal mucus velocity, a marker of lung mucociliary clearance, was significantly depressed in a dose-dependent manner with increasing smoke exposures. Results of bronchoalveolar lavages performed before and one day after the exposure showed that the smoke inhalation induced a severe inflammation with dramatic increases of inflammatory cells. The total number of cells per milliliter lavage return increased from 3.2 million to 25 million; percent neutrophils increased from 2.3 to 45.6% and percent macrophages decreased from 86 to 41%. These findings indicate that the side effects of smoke inhalation during intrabronchial laser surgery should not be neglected. The impairment of the defense mechanism of the lung combined with the inflammation as well as hypoxia might be fatal in compromised patients. Effective smoke removal devices should be developed to protect the patient as well as the surgeon.

Animals↗
PubMed1986

Ciliary responsiveness in allergic and nonallergic airways.

Allergic asthma is associated with airway (smooth muscle) hyperresponsiveness to several chemical mediators of anaphylaxis; however, it is not known whether this is accompanied by mucociliary hyperresponsiveness. The purpose of this study was therefore to determine if airway ciliary activity, a component function of mucociliary clearance, exhibits exaggerated responses to prostaglandin E1 (PGE1), prostaglandin E2 (PGE2), and leukotriene D4 (LTD4) in allergic sheep when compared with nonallergic sheep, and the effects of LTD4 are direct or involve the generation of cyclooxygenase products of arachidonate metabolism. Ciliary beat frequency (CBF) was measured in a perfusion chamber with a microscopic technique using tracheal epithelial cells obtained from brushing of "allergic" (positive cutaneous reaction and previous bronchospastic response to inhaled specific antigen) and "nonallergic" (negative cutaneous reaction, no previous inhalation challenge with antigen) sheep. Mean base-line CBF was not different among the groups; PGE1, PGE2, and LTD4 induced dose-dependent increases in CBF, and these increases were not different in allergic and nonallergic sheep. At the highest agonist concentration the mean increase in CBF from base line varied between 13 and 16% (P less than 0.05). The ciliostimulatory effect of LTD4 was significantly blunted by both the sulfidopeptide leukotriene antagonist FPL-55712 and the cyclooxygenase inhibitor indomethacin. These results suggest that allergic sheep fail to exhibit ciliary hyperresponsiveness to selected chemical mediators of anaphylaxis and the ciliostimulatory effect of LTD4 depends on the activation of cyclooxygenase and possibly the generation of prostaglandins.

Alprostadil↗
PubMed1983

Effects of chemical mediators of anaphylaxis on ciliary function.

We assessed the effects of selected chemical mediators of anaphylaxis on CBF in vitro. Ciliated epithelial cells were obtained from the trachea of conscious sheep with a cytology brush and suspended in a perfusion chamber containing KH. Ciliary activity was viewed microscopically and recorded on videotape for subsequent slow-motion analysis of CBF. Prostaglandin E1 (10(-8) M to 10(-6) M), prostaglandin E2 (10(-10) M to 10(-6) M), and leukotriene-C4 (10(-8) M) increased CBF between 7% and 33%. Histamine caused ciliostimulation only at the relatively high concentrations above 10(-5) M (7% increase in CBF), whereas prostaglandin F2 alpha (10(-10) M and 10(-6) M) was without effect. In no preparation was ciliary discoordination observed. These findings indicate that several chemical mediators of anaphylaxis stimulate CBF and that the previously described impairment of mucociliary transport in stable allergic asthma or antigen-induced bronchoconstriction is probably not caused by a primary alteration of ciliary function.

Alprostadil↗
PubMed1982

Role of ciliary motility in acute allergic mucociliary dysfunction.

The purpose of this investigation was to determine if abnormal ciliary function contributes to allergic mucociliary dysfunction. In conscious sheep with Ascaris suum hypersensitivity, ciliated cells were obtained with a cytology brush and tracheal mucous velocity (TMV) was determined before and serially for 2 h following antigen inhalation. The recovered cells (also containing mast cells) were suspended in a chamber, and ciliary activity was viewed microscopically and recorded on videotape for subsequent slow-motion analysis of ciliary beat frequency (CBF). One hour after A. suum challenge mean CBF (+/- SE) showed a slight increase from a base-line value of 630 +/- 16 to 716 +/- 30 beats/min (P less than 0.05) when mean TMV was decreased to 57% of base line (P less than 0.05). After 2 h, both mean CBF and TMV returned toward base line. Since possible in vivo actions of chemical mediators liberated by antigen challenge may have been lost after suspension of the brushed cells, we also assessed the effects of antigen on CBF in vitro. A. suum caused a dose-dependent increase in CBF that was blocked by cromolyn sodium. We conclude that 1) allergic mucociliary dysfunction is not caused by a decrease in CBF and 2) antigen-induced release of chemical mediators increases CBF.

Acute Disease↗
PubMed1980

Sulfur dioxide induced airway hyperreactivity in allergic sheep.

The effects of a four-hour exposure (via a Plexiglas hood) to sulfur dioxide (SO2) on airway reactivity was studied in both normal and allergic conscious sheep. Allergic sheep were defined as animals in whom inhalation of Ascaris suum extract resulted in an increase in mean pulmonary flow resistance (RL). Airway reactivity (delta RL) was assessed by measuring the increase in RL after 18 breaths of 0.25% carbachol, from an initial value obtained after 18 breaths of buffered saline. RL and delta RL were determined prior to, immediately after and 24 hours following SO2 exposure in three groups of sheep: six normal sheep exposed to 5 ppm SO2 (group A); six normal sheep exposed to 10 ppm SO2 (group B) and seven allergic sheep exposed to 5 ppm SO2 (group C). RL was not affected by SO2 exposure in any group but both groups B and C showed increases in delta RL 24 hours after exposure. Since the increase in delta RL was greater in group C than in either groups A or B, we conclude that allergic sheep have enhanced susceptibility to the injurious airway effects of SO2.

Airway Resistance↗
PubMed1976

[Osseous changes in Hodgkin's disease and cellular bone marrow infiltrations].

In 83 patients (40 females and 43 males) aged from 17 to 69 years belonging to 190 cases of Hodgkin's disease treated as inpatients in the Institute of Haematology in Warsaw in the years 1966-1974 radiological investigations of the skeletal system were done. In 17 cases (20.4%) bone changes were demonstrated appearing as rarefaction (9 cases), sclerosis (6 cases) or mixed (2 cases) changes. The changes were located most frequently in the spine, less frequently in the epiphyses of long bones and flat bones. All 17 cases with bone changes were qualified as IV clinical stage of disease progression. Radiological osseous changes were not pathognomonic and it was difficult to draw conclusions as to the mode of spread. Bone pains were present in 8 patients, including 7 with spinal changes. In some cases treated postmortem specific infiltrations were found in bone marrow.

Adolescent↗