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Abstract

Objective

To determine whether Pasteurella multocida toxin (PMT) affects growth of the proximal portion of the humerus of young pigs.

Animals

20 colostrum-deprived, cesarean-derived pigs.

Design and Procedure

5 groups (n = 4/group) of pigs were formed. Group-1 pigs received 0.1 ml of phosphate-buffered saline solution for 4 weeks; group-2 pigs received 0.05 μg of PMT/kg of body weight at 14 and 21 days; group-3 pigs received 0.05 μg of PMT/kg at 28 and 35 days; group-4 pigs received 0.1 μg of PMT/kg at 14 and 21 days; and group-5 pigs received hyperimmune serum (from a sow given purified toxin) on days 13, 20, 27, and 34, and 0.1 μg of PMT/kg on days 14, 21, 28, and 35.

Results

All pigs given 0.1 μg of PMT/kg without serum died or were euthanatized, as were 4 pigs given 0.05 μg of PMT/kg. These pigs had increased serum interleukin 1 and 6 bioactivities. Pigs surviving 0.05 μg of PMT had decreased weight gain, rough coat, marked atrophy of the ventral concha (as determined by turbinate perimeter ratios), and small stature. The surviving pigs also had reduced area and decreased proliferation indices in physeal chondrocytes on the basis of bromodeoxyuridine immunoreactivity. Control and serum-treated pigs gained weight, had no clinical effects, had similar physeal areas, and had higher cell proliferation indices.

Conclusions

PMT inhibits endochondral bone formation by reducing physeal area and chondrocyte proliferation in vivo. Hyperimmune serum neutralizes the effects of toxin on weight gain, clinical appearance, physeal area, and chondrocyte proliferation.

Clinical Relevance

PMT may affect growth of the skeletal system. Antiserum to PMT is protective. (Am J Vet Res 1996;57:848–852)

Free access
in American Journal of Veterinary Research

Abstract

Objective—To determine effects of the selectin inhibitor TBC1269 on neutrophil-mediated pulmonary damage during acute Mannheimia haemolytica-induced pneumonia in newborn calves.

Animals—Eighteen 1- to 3-day-old colostrumdeprived calves.

ProcedureMannheimia haemolytica or saline (0.9% NaCl) solution was inoculated in both cranial lung lobes of 12 and 6 calves, respectively. Calves were euthanatized 2 (saline, n = 3; M haemolytica, n = 4) or 6 hours (saline, n = 3; M haemolytica, n = 8) after inoculation. Four M haemolytica-inoculated calves euthanatized at 6 hours also received TBC1269 (25 mg/kg, IV) 30 minutes before and 2 hours after inoculation. Conjugated diene (CD) concentrations, inducible nitric oxide synthase (iNOS) expression, and apoptotic cell counts were determined in lung specimens collected during necropsy.

Results—Conjugated diene concentrations were significantly increased in all M haemolytica-inoculated groups, compared with saline-inoculated groups. Calves treated with TBC1269 had decreased concentrations of CD, compared with untreated calves, although the difference was not significant. Number of apoptotic neutrophils and macrophages increased significantly in TBC1269-treated calves, compared with untreated calves. Inducible nitric oxide synthase was expressed by epithelial cells and leukocytes. However, iNOS was less abundant in airway epithelial cells associated with inflammatory exudates. Degree of iNOS expression was similar between TBC1269-treated and untreated calves.

ConclusionsMannheimia haemolytica infection in neonatal calves resulted in pulmonary tissue damage and decreased epithelial cell iNOS expression. The selectin inhibitor TCB1269 altered, but did not completely inhibit, neutrophil-mediated pulmonary damage. ( Am J Vet Res 2001;62:17–22)

Full access
in American Journal of Veterinary Research

Abstract

Objectives—To determine effects of selectin inhibitor TBC1269 on neutrophil infiltration, and neutrophilassociated injury during pneumonia induced by Mannheimia haemolytica and concentration of antimicrobial anionic peptide (AAP) in bronchoalveolar lavage fluid (BALF) as well as antimicrobial activity of BALF from healthy (control) neonatal calves, neonatal calves with M haemolytica-induced pneumonia, neonatal calves with prior treatment with TBC1269, and adult cattle.

Animals—Eighteen 1- to 3-day-old calves and 9 adult cattle.

Procedure—Calves were inoculated with M haemolyticaor pyrogen-free saline (0.14M NaCl) solution into the right cranial lung lobe, and BALF was collected 2 or 6 hours after inoculation. Thirty minutes before and 2 hours after inoculation, 4 calves received TBC1269. The BALF collected from 9 adult cattle was used for comparison of BALF AAP concentration and antimicrobial activity. Protein concentration and neutrophil differential percentage and degeneration in BALF were determined. An ELISA and killing assay were used to determine BALF AAP concentration and antimicrobial activity, respectively.

Results—Total protein concentration was significantly decreased in BALF from calves receiving TBC1269. Similar concentrations of AAP were detected in BALF from all calves, which were 3-fold higher than those in BALF from adult cattle. However, BALF from neonates had little or no anti-M haemolytica activity.

Conclusions and Clinical Relevance—These results suggest that TBC1269 decreases pulmonary tissue injury in neonatal calves infected with M haemolytica. Although AAP is detectable in neonatal BALF at 3 times the concentration detected in adult BALF, neonatal BALF lacks antimicrobial activity for M haemolytica. (Am J Vet Res 2001;62:665–672)

Full access
in American Journal of Veterinary Research

Abstract

Objective—To measure serum calprotectin concentration in dogs with inflammatory bowel disease (IBD) before and after initiation of treatment and evaluate its correlation with a clinical scoring system (canine IBD activity index), serum canine C-reactive protein concentration, and severity of histopathologic changes.

Animals—34 dogs with idiopathic IBD and 139 healthy control dogs.

Procedures—From dogs with IBD, blood samples were collected immediately before (baseline) and 3 weeks after initiation of 1 of 2 treatments: prednisone (1 mg/kg, PO, q 12 h; n = 21) or a combination of prednisone and metronidazole (10 mg/kg, PO, q 12 h; 13). Blood samples were collected once from each of the control dogs. For all samples, serum calprotectin concentration was determined via radioimmunoassay.

Results—Mean serum calprotectin concentrations for dogs with IBD at baseline (431.1 μg/L) and 3 weeks after initiation of treatment (676.9 μg/L) were significantly higher, compared with that (219.4 μg/L) for control dogs, and were not significantly correlated with the canine IBD activity index, serum C-reactive protein concentration, or severity of histopathologic changes. The use of a serum calprotectin concentration of ≥ 296.0 μg/L as a cutoff had a sensitivity of 82.4% (95% confidence interval, 65.5% to 93.2%) and specificity of 68.4% (95% confidence interval, 59.9% to 76.0%) for distinguishing dogs with idiopathic IBD from healthy dogs.

Conclusions and Clinical Relevance—Serum calprotectin concentration may be a useful biomarker for the detection of inflammation in dogs, but the use of certain drugs (eg, glucocorticoids) appears to limit its clinical usefulness.

Full access
in American Journal of Veterinary Research

SUMMARY

Leukocytosis (34,600 wbc/μl of blood) was detected in an apparently healthy 7-day-old Holstein heifer. Analysis of blood samples obtained over the next 41 days revealed chronic progressive neutrophilia, which peaked at > 85% neutrophils and exceeded 100,000 wbc/μl. In vitro assessment of isolated blood neutrophils obtained from the heifer at 38 and 45 days of age revealed selected functional abnormalities. Endocytosis of immunoglobulin-opsonized Staphylococcus aureus and killing of this test organism by the calf’s neutrophils were significantly diminished, as were phagocytosis-associated superoxide generation, chemiluminescence activity, and myeloperoxidase-catalyzed iodination. Diminished H2O2 elaboration by the calf’s neutrophils was evident during ingestion of opsonized zymosan or on exposure to phorbol myristate acetate. Extracellular release (secretion) of elastase during ingestion of zymosan was also diminished, although total cell content of elastase was normal, compared with that of neutrophils from age-matched calves, and granular or other morphologic abnormalities of the calf’s neutrophils were not evident by ultrastructural examination. Abnormalities of random migration were inconsistently detected, and normal or high degree of antibody-dependent cytotoxicity or natural killing by the calf’s neutrophils was observed. Similar in vitro assessment of neutrophils obtained from the calf’s dam revealed no functional abnormalities. The calf died at 48 days of age, with persistent fever and chronic diarrhea, despite administration of antibiotics. Histologic examination at necropsy revealed large numbers of intravascular neutrophils in most tissues, including massive neutrophil sequestration in spleen. However, a striking lack of extravascular neutrophils was evident in inflamed submucosa adjacent to intestinal ulcers heavily contaminated with enteric microorganisms. Bone marrow examination revealed diffuse myeloid hyperplasia, but no other abnormalities.

The clinical and pathologic features in this calf were similar to those in previously reported human patients or Irish Setters with genetic deficiency of the CD11/CD18 leukocyte glycoprotein complex, thus prompting further postmortem evaluations. Results of immunoblot analyses of the neutrophil lysates of the heifer calf (isolated and stored prior to death) documented severe deficiency of Mac-1 (CD11b/CD18). Results of immunofluorescent analyses indicated substantially diminished (intermediate) amounts ofthe Mac-1 β subunit (CD18) on blood neutrophils of the calf's dam and sire and on neutrophils of 8 of 15 paternal half-siblings; findings were consistent with an autosomal recessive trait in the proband's kindred. Findings also indicate that genetic abnormalities of CD11/CD18 proteins may underlie the molecular pathogenesis of disease in this calf as well as other previously described examples of the granulocytopathy syndrome in Holstein cattle.

Free access
in American Journal of Veterinary Research

Abstract

Objective—To characterize mucosal gene expression in dogs with chronic enteropathy (CE).

Animals—18 dogs with CE and 6 healthy control dogs.

Procedures—Small intestinal mucosal biopsy specimens were endoscopically obtained from dogs. Disease severity in dogs with CE was determined via inflammatory bowel index scores and histologic grading of biopsy specimens. Total RNA was extracted from biopsy specimens and microchip array analysis (approx 43,000 probe sets) and quantitative reverse transcriptase PCR assays were performed.

Results—1,875 genes were differentially expressed between dogs with CE and healthy control dogs; 1,582 (85%) genes were downregulated in dogs with CE, including neurotensin, fatty acid–binding protein 6, fatty acid synthase, aldehyde dehydrogenase 1 family member B1, metallothionein, and claudin 8, whereas few genes were upregulated in dogs with CE, including genes encoding products involved in extracellular matrix degradation (matrix metallopeptidases 1, 3, and 13), inflammation (tumor necrosis factor, interleukin-8, peroxisome proliferator–activated receptor γ, and S100 calcium-binding protein G), iron transport (solute carrier family 40 member 1), and immunity (CD96 and carcinoembryonic antigen–related cell adhesion molecule [CEACAM] 18). Dogs with CE and protein-losing enteropathy had the greatest number of differentially expressed genes. Results of quantitative reverse transcriptase PCR assay for select genes were similar to those for microchip array analysis.

Conclusions and Clinical Relevance—Expression of genes encoding products regulating mucosal inflammation was altered in dogs with CE and varied with disease severity.

Impact for Human Medicine—Molecular pathogenesis of CE in dogs may be similar to that in humans with inflammatory bowel disease.

Full access
in American Journal of Veterinary Research