Changes in electrolytes and uric acid excretion during and after a 100 km run.

Physical activity leads to changes in water and electrolyte homeostasis and to enhanced purine metabolism. The typical abnormalities observed after exercise are hyperkaliemia, hyper- or hyponatremia and hyperuricemia. The possible explanations of hyperuricemia are: increased metabolism and decreased elimination of uric acid. Changes in uric acid excretion are commonly observed in disturbances of sodium and water homeostasis. The aim of this study was to evaluate changes in electrolytes and uric acid excretion during a very long period of exercise. Twenty subjects with a mean age of 40.75±7.15 years took part in a 100 km run. The route of the run was based on the university stadium track. All subjects were experienced amateur runners, with a mean time of regular running of 6.11±7.19 years. Blood was collected before the start, after every 25 km and 12 hours after the run. The levels of electrolytes, creatinine, uric acid, cortisol, aldosterone, creatine kinase, C-reactive protein and interleukin-6 were measured. Creatinine clearance, urinary potassium-to-sodium ratio, fractional excretion of electrolytes and uric acid were calculated. Seventeen runners completed the study. Significant increases in sodium (from 141.65±1.90 to 144.29±3.65mmol/l), potassium (from 4.53±0.34 to 5.03±0.42mmol/l), creatinine (from 0.88±0.11 to 1.10±0.20mg/dl) and uric acid (from 5.15±0.87 to 5.94±1.50 mg/dl) were observed after 100 km (p less than 0.05). Other significant changes during the study were noted in fractional excretions of sodium (from 0.86±0.29 to 0.33±0.13%) and potassium (from 6.66±2.79 to 18.90±10.01%), probably reflecting the decrease in renal blood flow (RBF) and increase in renal tubule reabsorption. The fractional excretion of uric acid slightly increased but without statistical significance from 5.34±1.51 to 6.09±2.34%. The results of our study showed that during very long but not very intensive exercise there is no change in uric acid excretion, although at the same time profound changes in electrolyte excretion are found. Both hyperuricemia and hyperuricosuria may be harmful, therefore it seems logical that the best way to avoid those abnormalities is to maintain fractional uric acid excretion.

Paired Analysis of Outcomes After Kidney Transplantation in Peritoneal and Hemodialysis Patients.

BACKGROUND: The impact of dialysis modality before kidney transplantation (hemodialysis or peritoneal dialysis) on outcomes is not clear. In this study we retrospectively analyzed the impact of dialysis modality on posttransplant follow-up. METHODS: To minimize donor bias, a paired kidney analysis was applied. One hundred thirty-three pairs of peritoneal dialysis (PD) and hemodialysis (HD) patients were transplanted at our center between 1994 and 2016. Those who received kidneys from the same donor were included in the study. HD patients were significantly older (44 vs 48 years), but the Charlson Comorbidity Index was similar (3.12 vs 3.46) in both groups. The groups did not differ significantly with respect to immunosuppressive protocols and number of mismatches (2.96 vs 2.95). RESULTS: One-year patient (98% vs 96%) and graft (90% vs 93%) survival was similar in the PD and HD patient groups. The Kaplan-Meier curves of the patients and graft survival did not differ significantly. Delayed graft function (DGF) and acute rejection (AR) occurred significantly more often in the HD recipients. Graft vessel thrombosis resulting in graft loss occurred in 9 PD (6.7%) and 4 HD (3%) patients (P > .05). Serum creatinine concentration and estimated glomerular filtration rate (using the Modification of Diet in Renal Disease guidelines) showed no difference at 1 month, 1 year, and at final visit. On multivariate analysis, factors significantly associated with graft loss were graft vessel thrombosis, DGF, and graft function 1 month after transplantation. On univariate analysis, age, coronary heart disease, and graft loss were associated with death. Among these factors, only coronary heart disease (model 1) and graft loss were significant predictors of death on multivariate analysis. CONCLUSION: The long-term outcome for renal transplantation is similar in patients with PD and HD. These groups differ in some aspects, however, such as susceptibility to vascular thrombosis in PD patients, and to DGF and AR in HD patients.

Impact of Obesity on Renal Graft Function-Analysis of Kidney Grafts From the Same Donor.

BACKGROUND: The epidemic of obesity has led to dilemmas facing all nephrologists who care for patients with chronic kidney disease and who must make decisions regarding whether or not the patient can undergo transplantation. The aim of the study was to assess the outcome of transplantation among obese compared to nonobese recipients. To minimize donor variability and bias, paired kidney analysis was applied. MATERIALS AND METHODS: Patients with a body mass index >30 who received transplants in our unit between January 2000 and December 2010 were selected. For the analysis, only obese transplant recipients (OTR) and their kidney donor pairs with a body mass index <30 (nonobese transplant recipients [NOTR]) were selected. A total of 37 pairs of patients were evaluated in terms of the graft function, patient and graft survival, and number of complications. RESULTS: Groups did not differ with respect to sex and comorbidities. OTR were older than NOTR (53.1 vs 46.02 years old, P < .05). One-year patient and graft survivals were similar (100% vs 97.29% and 100% vs 94.59% in OTR and NOTR, respectively). There were no significant differences between OTR and NOTR with respect to incidence of acute rejection (29.7% vs 18.9%), delayed graft function (35.13% vs 29.72%), and mean serum creatinine and estimated glomerular filtration rate (four-variable Modification of Diet in Renal Disease formula) assessed at discharge and after 3, 6, and 12 months, respectively. OTR had a significantly longer hospitalization time (25.56 vs 20.66 days; P < .05), and more often experienced wound breakdown (32.43% vs 8.1%; P < .05) and new-onset diabetes after transplantation (57.14% vs 6.25%; P < .05). CONCLUSIONS: Obesity did not negatively influence patient and graft survival. Transplantation in obese patients should not be postponed.

Gastrointestinal Pathologies in Patients After Successful Renal Transplantation-A Pilot Study.

BACKGROUND: The beneficial effect of kidney transplantation in patients requiring continuous renal replacement therapy owing to chronic kidney disease is well known and accepted. Kidney transplantation protects the patient from complications that may develop during chronic dialysis. Unfortunately, there is also evidence that kidney transplant patients are more prone to developing cancer than healthy persons. The aim of this study was to evaluate the prevalence of gastrointestinal pathologies in patients after kidney transplantation. METHODS: Adult patients after kidney transplantation, who are under the care of the Outpatient Department of Nephrology in Gdansk, received alarm symptom questionnaires and referral for testing for the presence of fecal occult blood. Then, in 45 selected patients (29 men and 16 women) endoscopic examination was performed. Mean age was 57.6 ± 10.1 (range, 35-83) years. RESULTS: Out of ∼940 patients after kidney transplantation, resting under supervision of outpatient department, 181 patients completed the questionnaire and 100 gave a stool sample for testing: 32 results were positive. After analyzing the questionnaires and stool results, 88 patients were qualified for further investigation. The endoscopic examination had been performed so far in 45 patients and revealed gastritis and/or duodenitis in 33 patients, diverticular colon disease in 18, esophagitis in 8, colon polyps in 14, stomach polyps in 3, inflammatory bowel disease in 7, and cancers in 3. CONCLUSIONS: The preliminary results indicate that patients after kidney transplantation have significant risk of gastrointestinal pathologies and require detailed diagnostic endoscopy.

Liver Transplantation for Incurable Alveolar Echinococcosis: An Analysis of Patients Hospitalized in Department of Tropical and Parasitic Diseases in Gdynia.

INTRODUCTION: Alveolar echinococcosis is a parasitic disease caused by the larval stage of tapeworm Echinococcus multilocularis. It usually involves the liver, but can spread to other organs. The treatment of choice is a surgical resection supported by antiparasitic drugs. In the advanced stages of the disease a liver transplantation is the only option. AIM: This article presents the problems related to care of patients after liver transplantation for advanced alveolar echinococcosis. MATERIAL: Sixty-seven patients with alveolar echinococcosis were hospitalized in our clinic in the years 2000-2015. Liver transplantation has been a therapeutic option for 9 patients. We retrospectively analyzed data of qualification for the liver transplantation and the postoperative treatment. RESULTS: Follow-up time after liver transplantation ranged from 7 months to 155 months (average, 6.4 years). One patient, with a history of advanced disease (P4N1M0), died due to liver failure. One patient was lost to follow-up. After liver transplantation all patients were receiving albendazole treatment. Two patients did not follow the medical recommendations. In 1 patient, who decided to stop therapy after 1 year, the relapse of alveolar echinococcosis in the left lobe of the transplanted liver passing through the diaphragm to the pericardium was detected. In another case we suspected a relapse of alveolar echinococcosis in transplanted liver due to positive serological tests. CONCLUSION: The prognosis of patient after liver transplantation for alveolar echinococcosis is good. The main problem caused by immunosuppressive therapy is a recurrence of disease in the transplanted liver.

Renal transplantation in dialysis patients with the history of coronary artery bypass grafting and cardiac valve replacement.

Death with a functioning kidney is the most frequent cause of graft failure. Cardiovascular disease is the most frequent cause of death after renal transplantation. Therefore, prior to grafting, it is mandatory to diagnose and treat coronary artery disease and heart valve impairment. Transplantation is the best option for renal replacement therapy as far as the quality of life and life expectancy are concerned, although patients with such comorbidities may experience a higher short-term mortality risk. The objective for this study was to analyze both short- and long-term results of patients after coronary artery bypass grafting (CABG) or cardiac valve replacement (CVR). The cardiac surgery recipient group (CSR) included 16 patients (15 men, 1 woman) aged from 44 to 73 (mean 54.9 +/- 7.8) years. CABG was performed in 13/16 patients, and CVR in 3/16. The rest of our patients were treated as a comparative noncardiac surgery recipient (non-CSR) group. It consisted of 422 patients (264 men, 158 women) aged from 14 to 68 years (mean 43.2 +/- 12.9). The comparison revealed that graft function estimated at 1 year after transplantation was not different: serum creatinine concentrations of 1.7 +/- 0.2 and 1.6 +/- 0.5 mg/dL in CSR and non-CSR, respectively. One-year patient survival in the CVR group of 93.8% was slightly worse than that in the non-CSR group (97.9%), but death-censored 1-year graft survivals were comparable in both groups (93.8% vs 92%). Urinary tract and cytomegalovirus infections were the most common complications in the CSR group. One patient lost his graft in month 3(rd) due to many serious infectious complications. One patient died at the end of 12 months as a result of a cardiovascular event (1/16). Our single-center results confirm that transplantation in patients after CABG or CVR is a safe procedure; therefore, such patients should be referred into the waiting list.

A single center experience in preemptive kidney transplantation.

Transplantation is recognized as preemptive if it takes place before the initiation of chronic dialysis. This maneuver has the potential to avoid the morbidity and burden of chronic dialysis. From November 2003 to April 2005, 15 (7 male, 8 female) end-stage renal failure patients of mean age 40 +/- 14.8 years received preemptive grafts from 2 living-related and 13 cadaveric donors, constituting 11.5% of all kidney transplantations performed in our center at that time. The period on the waiting list for preemptive recipients, namely, 2 weeks to 6 months (mean, 2.4 months), was significantly shorter than that of other patients (mean, 13.8 months). The mean creatinine clearance calculated from the Cockroft Gault formula and the mean plasma creatinine level in preemptive recipients before transplantation were 12.7 +/- 3.1 mL/min and 6.6 +/- 0.8 mg/dL, respectively. The donors for preemptive and non-preemptive groups of recipients did not differ significantly in respect to age, gender, and renal function. The mean number of mismatches of 3.73 and 3.25 and the mean total ischemic times of 9.53 +/- 5 and 11.2 +/- 5 hours, in preemptive and non-preemptive groups of recipients, respectively. The incidence of delayed graft function (dialysis in the first week after transplantation) was significantly lower among preemptive recipients (20% versus 42%, respectively). The groups did not differ either in respect to the occurrence of acute rejection episodes or graft and patient survivals. In preemptive patients the mean plasma creatinine levels at 3 and 12 months were 1.37 +/- 0.3 and 1.09 +/- 0.3 mg/dL, and in non-preemptive patients 1.7 +/- 0.5 and 1.4 +/- 0.4 mg/dL. In conclusion, these results are promising, confirming the notion that preemptive kidney transplantation is the optimal treatment for end-stage renal disease patients.

Increased rate of cholesterologenesis--a possible cause of hypercholesterolemia in experimental chronic renal failure in rats.

Hypercholesterolemia plays an important role in the lipid abnormalities in chronic renal failure (CRF). It is thought to contribute to both a progression of renal failure and atherosclerosis. Despite intensive research, the etiopathogenesis of hypercholesterolemia in CRF patients is still obscure. The present study was designed to evaluate the possible role of cholesterol overproduction in the development of hypercholesterolemia associated with experimental CRF. We found that plasma total cholesterol and cholesterol distributed in VLDL, LDL and HDL concentrations were significantly enhanced in CRF rats. Simultaneously, the rate of liver cholesterol biosynthesis in vivo (measured by determining the incorporation of tritium from tritiated water intraperitoneally injected into cholesterol ), liver microsomal 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity and liver HMG-CoA reductase mRNA presence were elevated. Significant increases in activity of liver malic enzyme, glucose 6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase, NADPH-producing enzyme (required for cholesterol synthesis) have also been observed in CRF rats. In conclusion, the increased rate of liver cholesterol biosynthesis due to increase of HMG-CoA reductase and NADPH-producing enzyme gene expression could be one of the possible causes of hypercholesterolemia in CRF animals.

Proinflammatory roles of T-cell receptor (TCR)gammadelta and TCRalphabeta lymphocytes in a murine model of asthma.

The role of lymphocytes bearing alphabeta or gammadelta T-cell receptors (TCRs) was assessed during the acute allergic response in a mouse model of asthma. The inflammatory immune response to ovalbumin (OVA) was characterized in wild-type C57BL/6J mice and congenic TCRbeta(-/-) and TCRdelta(-/-) mice by evaluation of airway eosinophilia, histopathology, serum immunoglobulin (Ig)E levels, and in vivo airway responsiveness to methacholine. OVA-challenged wild-type mice demonstrated marked pulmonary inflammation, evidenced by airway eosinophilia (68 +/- 7 x 10(4) cells), peribronchial lympho-plasmocytic infiltration, and elevated serum IgE (4.9 +/- 0.6 microg/ml). These responses were markedly attenuated in TCRdelta(-/-) animals (5.0 +/- 1.0 x 10(4) eosinophils and 1.6 +/- 0. 3 microg/ml IgE) and were completely absent in TCRbeta(-/-) mice (< 1 x 10(3) eosinophils and 0.38 +/- 0.21 microg/ml IgE). Similar results were observed in mice treated with anti-TCRgammadelta or anti-TCRalphabeta monoclonal antibodies. Airway responsiveness to aerosolized methacholine was also reduced in challenged TCRdelta(-/-) animals relative to challenged wild-type mice. These results demonstrate that acute allergic airway responses are dependent upon intact TCRalphabeta and TCRgammadelta lymphocyte function and that TCRgammadelta cells promote acute airway sensitization.

[Acute iatrogenic postrenal failure]. / Ostra jatrogenna ponerkowa niewydolnosc nerek.

Urinary tract obstruction is relatively seldom responsible for causing acute renal failure. It is also known that the iatrogenic factors account for very small percent of all episodes of obstructive renal failure. This report concerns a patient with acute renal failure due to improper urinary catheter use. It was followed by inattentive and nonchalant examinations taken by urologist in spite of the evident symptoms of acute obstructive renal insufficiency. The authors emphasize the importance of properly taken patient's history and physical examination to prevent patients from fatal courses of diseases. It is also sufficient to avoid difficult ethical problems and to protect ourselves from unpleasant legal consequences.

Repeated measurement of intestinal permeability as an assessment of colitis severity in HLA-B27 transgenic rats.

We report on the development of a method for repeated monitoring of mucosal permeability that allows assessment of the severity of colitis and evaluation of treatment efficacy in HLA-B27 transgenic rats. We determined the extent to which intestinal permeability related to stool condition, colon weight, and histological pathology in precolitic and diseased rats up to 29 weeks old. Intestinal permeability was measured by the urinary excretion of iodixanol at 24 h after oral administration. Mean permeability values increased significantly with age in HLA-B27 rats but remained decreased in the background strain Fischer-344 (F-344) control animals. Macroscopic evaluation of HLA-B27 rat colons between 20 and 24 weeks old showed colonic thickening with colonic wet weights increased from 3.4+/-0.13 mg/kg b.wt. in F-344 rats to 6.79+/-0.73 mg/kg b.wt. (p<.05) in HLA-B27 rats. Histological examination of HLA-B27 rat colons confirmed the colonic inflammation as a chronic active mononuclear cell infiltrate. The increase in colon weight was associated with an increase in permeability: 1.16+/-0.17 mg iodixanol versus 5.37+/-1.3 mg of iodixanol in F-344 and HLA-B27 rats, respectively. Three weeks treatment of HLA-B27 rats with cyclosporin A, but not sulfasalazine, showed a dose-dependent decrease in mucosal permeability and colon weight. Neither treatment improved stool condition. We conclude that the measurement of intestinal permeability by iodixanol excretion is a useful biochemical marker that is associated with increases in colonic weight and histological evaluation of inflammation. These data indicate that this technique may be valuable for diagnostic and evaluation purposes in preclinical models of inflammatory bowel disease.

Shifts in lung lymphocyte profiles correlate with the sequential development of acute allergic and chronic tolerant stages in a murine asthma model.

T lymphocytes have a central regulatory role in the pathogenesis of asthma. We delineated the participation of lymphocytes in the acute allergic and chronic tolerant stages of a murine model of asthma by characterizing the various subsets of lymphocytes in bronchoalveolar lavage and lung tissue associated with these responses. Acute (10-day) aerosol challenge of immunized C57BL/6J mice with ovalbumin resulted in airway eosinophilia, histological evidence of peribronchial and perivascular airway inflammation, clusters of B cells and TCRgammadelta cells in lung tissue, increased serum IgE levels, and airway hyperresponsiveness to methacholine. In mice subjected to chronic (6-week) aerosol challenge with ovalbumin, airway inflammation and serum IgE levels were significantly attenuated and airway hyperresponsiveness was absent. The marked increases in lung B and T cell populations seen in the acute stage were also significantly reduced in the chronic stage of this model. Thus, acute ovalbumin challenge resulted in airway sensitization characteristic of asthma, whereas chronic ovalbumin challenge elicited a suppressed or tolerant state. The transition from antigenic sensitization to tolerance was accompanied by shifts in lymphocyte profiles in the lung and bronchoalveolar lavage fluid.

Contribution of nitric oxide synthases 1, 2, and 3 to airway hyperresponsiveness and inflammation in a murine model of asthma.

Asthma is a chronic disease characterized by increased airway responsiveness and airway inflammation. The functional role of nitric oxide (NO) and the various nitric oxide synthase (NOS) isoforms in human asthma is controversial. To investigate the role of NO in an established model of allergic asthma, mice with targeted deletions of the three known isoforms of NOS (NOS1, 2, and 3) were studied. Although the inducible (NOS2) isoform was significantly upregulated in the lungs of ovalbumin (OVA)-sensitized and -challenged (OVA/OVA) wild-type (WT) mice and was undetectable in similarly treated NOS2-deficient mice, airway responsiveness was not significantly different between these groups. OVA/OVA endothelial (NOS3)-deficient mice were significantly more responsive to methacholine challenge compared with similarly treated NOS1 and NOS1&3-deficient mice. Airway responsiveness in OVA/OVA neuronal (NOS1)-deficient and neuronal/endothelial (NOS1&3) double-deficient mice was significantly less than that observed in similarly treated NOS2 and WT groups. These findings demonstrate an important function for the nNOS isoform in controlling the inducibility of airway hyperresponsiveness in this model of allergic asthma.

Interleukin-8 receptor modulates IgE production and B-cell expansion and trafficking in allergen-induced pulmonary inflammation.

We examined the role of the interleukin-8 (IL-8) receptor in a murine model of allergen-induced pulmonary inflammation using mice with a targeted deletion of the murine IL-8 receptor homologue (IL-8r-/-). Wild-type (Wt) and IL-8r-/- mice were systemically immunized to ovalbumin (OVA) and were exposed with either single or multiple challenge of aerosolized phosphate-buffered saline (OVA/PBS) or OVA (OVA/OVA). Analysis of cells recovered from bronchoalveolar lavage (BAL) revealed a diminished recruitment of neutrophils to the airway lumen after single challenge in IL-8r-/- mice compared with Wt mice, whereas multiply challenged IL-8r-/- mice had increased B cells and fewer neutrophils compared with Wt mice. Both Wt and IL-8r-/- OVA/OVA mice recruited similar numbers of eosinophils to the BAL fluid and exhibited comparable degrees of pulmonary inflammation histologically. Both total and OVA-specific IgE levels were greater in multiply challenged IL-8r-/- OVA/OVA mice than in Wt mice. Both the IL-8r-/- OVA/OVA and OVA/PBS mice were significantly less responsive to methacholine than their respective Wt groups, but both Wt and IL-8r mice showed similar degrees of enhancement after multiple allergen challenge. The data demonstrate that the IL-8r modulates IgE production, airway responsiveness, and the composition of the cells (B cells and neutrophils) recruited to the airway lumen in response to antigen.

Reduction of antigen-induced airway hyperreactivity and eosinophilia in ICAM-1-deficient mice.

A murine model of asthma is described in which we examined the role of intercellular adhesion molecule-1 (ICAM-1) in the pathogenesis of airway reactivity, pulmonary eosinophilia, and inflammation. We sensitized wild-type control [C57BL/6J, (+/+)] and ICAM-1 knockout [C57BL/6J-ICAM-1, (-/-)] mice to ovalbumin (OVA), and challenged them with OVA delivered by aerosol (OVA-OVA) to induce a phenotype consistent with an asthmatic response. Bronchial responsiveness to methacholine and counts of cell numbers and measurements of eosinophil content and cytokine levels in bronchoalveolar lavage fluid (BALF) were significantly attenuated in ICAM-1(-/-) mice as compared with (+/+) mice. We also showed that the absence of ICAM-1 had no significant affects on the production of serum IgE antibody, but did have an effect on ex vivo lymphocyte proliferation. Additionally, immunohistochemistry: (1) revealed increased staining for vascular cell adhesion molecule-1 (VCAM-1) after antigen challenge in the ICAM-1(-/-) mice but not in the ICAM-1(+/+) controls; and (2) confirmed the presence of alternatively spliced forms of ICAM-1 in the lungs of ICAM-1(-/-) mice. Thus, despite the availability of alternate adhesion pathways in ICAM-1(-/-) mice, the absence of ICAM-1 prevented eosinophils from entering the airways. In summary, we found that the ICAM-1 knockout mice exhibited a significantly inhibited response to aerosol antigen challenge for most of the parameters examined, and conclude that ICAM-1 is an important ligand mediating T-cell proliferation in response to antigen, eosinophil migration into the airways, and the development of airway hyperreactivity (AHR) in allergen-sensitized and -challenged mice.

Reduction of allergic airway responses in P-selectin-deficient mice.

P-selectin is an adhesion receptor that has been shown to be important in the recruitment of eosinophils and lymphocytes in a variety of inflammatory conditions. Because cellular recruitment is thought to be a critical event in allergen-induced changes in airway responsiveness, we reasoned that P-selectin-deficient mice would exhibit reduced airway responsiveness and cellular trafficking noted in wild-type (+/+) mice. Both (+/+) and P-selectin-deficient (-/-) mice sensitized and challenged with ovalbumin (OVA/OVA) exhibited the same capacity to produce increased titers of total and OVA-specific immunoglobulin E. Airway responsiveness to methacholine was significantly greater in the (+/+) (OVA/OVA) animals than it was in the respective (-/-) (OVA/OVA) group or control groups (P = 0.0016). Bronchoalveolar lavage fluid from (-/-) (OVA/OVA) mice contained significantly fewer eosinophils and lymphocytes compared with the (+/+) (OVA/OVA) mice (P < 0.05). These results suggest that the predominant role of P-selectin in OVA-induced airway hyperresponsiveness is to promote the airway inflammatory response to allergen inhalation.

Nonatopic asthma: in vivo airway hyperreactivity adoptively transferred to naive mice by THY-1(+) and B220(+) antigen-specific cells that lack surface expression of CD3.

To investigate the cellular immune events contributing to airway hyperreactivity (AHR), we studied an in vivo mouse model induced by the hapten picryl (trinitrophenyl) chloride (PCl). Mice were immunized by cutaneous contact sensitization with PCl and airway challenged subsequently with picryl sulfonic acid (PSA) antigen (Ag). Increased airway resistance was produced late (24 h) after Ag challenge, disappeared by 48 h, and was associated with no decrease in diffusion capacity. AHR could be produced in PCl immune/ PSA challenged mice on day 7 or even, with challenge, as early as 1 d after contact sensitization, after adoptive transfer of immune cells lacking CD3(+) contact sensitivity effector T cells, or after transfer of Ag-specific lymphoid cells depleted of conventional T lymphocytes with surface determinants for CD3, CD4, CD8, TCR-beta, or TCR-delta molecules. Further experiments showed that development of AHR depended upon transfer of immune cells expressing surface membrane Thy-1 and B220 (CD45RA) determinants. We concluded that a novel population of Ag-specific lymphoid cells with a defined surface phenotype (Thy-1(+), CD3(-), CD4(-), CD8(-), TCR-alphabeta-, TCR-gammadelta-, and CD45RA+) is required in a mouse model for the development of AHR.

Intercellular adhesion molecule-1 contributes to pulmonary oxygen toxicity in mice: role of leukocytes revised.

In immature or injured lungs, impaired alveolar gas exchange forces the use of elevated levels of inhaled oxygen to maintain life. But, at high concentrations oxygen induces lung injury, edema, and bronchopulmonary dysplasia, probably by stimulating the generation of reactive oxygen radicals and subsequent neutrophil infiltration. In addition to regulating neutrophil diapedesis, intercellular adhesion molecule-1 (ICAM-1) expression is marked on inflamed alveolar epithelium, suggesting a role for ICAM-1 in oxygen-induced, neutrophil-mediated parenchymal damage. To test this, we evaluated the rat anti-mouse ICAM-1 monoclonal antibody YN1/1.7 in 2 protocols of oxygen-induced toxicity in adult, male Balb-c mice: greater than or equal to 95% O2 for 84 hr and greater than or equal to 95% O2 for 60 hr followed by 48 hr at 21% (ambient) O2. YN1/1.7 treatment partially attenuated the neutrophil infiltration, lung damage (lavage lactate dehydrogenase [LDH] activity) and dysfunction (reductions in respiratory system compliance [Crs] and diffusion capacity of the lungs for carbon monoxide [DLCO] in the 84 hr exposure protocol. In the milder 60 hr exposure protocol, YN1/1.7 completely blocked the oxygen-induced lung dysfunction (reductions in Crs and DLco). These results confirm the contribution of leukocytes in the pathogenesis of pulmonary oxygen toxicity and indicate that antagonism of ICAM-1 may provide a therapeutic approach to reducing hyperoxic lung injury and dysfunction.

BI-L-239, a 5-lipoxygenase inhibitor, blocks inhaled antigen-induced airway hyperresponsiveness in conscious guinea pigs.

Male Hartley guinea pigs were actively sensitized to ovalbumin (OA). Respiratory system resistance (Rrs) was measured by forced oscillations superimposed on tidal breathing. Airway responsiveness (inhaled methacholine PC100) was determined three days prior and three days after (day 10) three alternate day inhalations of OA. Airway cell composition was assessed on day 10 by lung lavage. Three groups (n = 5-6) were studied: A) vehicle challenged, B) OA challenged/placebo treated, C) OA challenged/BI-L-239 (2,6-dimethyl-4-[2-(4-fluorophenyl)ethenyl]phenol) treated (10 x 0.75 mg/actuation, 10 minutes prior to each OA challenge). Animals were treated with pyrilamine and indomethacin (10 mg/kg i.p.) 30 minutes prior to each OA challenge. OA induced acute increases in Rrs of 143 +/- 29%, 238 +/- 73% and 102 +/- 43% in placebo and 86 +/- 34%, 45 +/- 35% (p, 0.05 vs. placebo) and 102 +/- 31% in BI-L-239 treated. OA induced a significant (p less than 0.05) increase in airway leukocytes in placebo (487 +/- 36 to 1615 +/- 421 x 10(3)/ml) but not BI-L-239 treated (to 881 +/- 155 x 10(3)/ml) and decrease in methacholine PC100 in placebo (1.487 +/- 0.49 to 0.39 +/- 0.18 mg/ml) but not BI-L-239 treated (0.99 +/- 34 to 1.04 +/- 0.39 mg/ml). We conclude that BI-L-239 attenuates the airway constriction, inflammation and hyperresponsiveness induced by repeated antigen inhalations in conscious guinea pigs.