Comparative analysis of the aberrant immunophenotype and clinical characteristics in dogs with lymphoma: a study of 27 cases.

Introduction: Aberrant lymphoma phenotypes are frequently found in dogs, but the clinical implications are sparse. Methods: Twenty-seven dogs with aberrant lymphoma diagnosed using flow cytometry between 2017 and 2023 were analyzed. Major paraneoplastic syndromes, prognostic factors, and clinical features of lymphoma were compared to their immunophenotypes. Results: Twenty-seven dogs had aberrant immunophenotypes, with MHCII- (48%) and CD3+/CD21+ (44%) being the most commonly identified aberrancies. In B-cell lymphoma, the most frequent aberrancies were MHC II- (53%), CD3+/CD21+ (41%), CD34+ (24%), and CD79a- (24%). Meanwhile, in T-cell lymphoma, CD3+/CD21+ (63%), CD4-/CD8-(50%), CD5- (50%), and CD45- (50%) were the most common. The platelet-neutrophil ratio was significantly higher in the CD3+/CD21+ group than in the other groups, where either one or both markers were not expressed (55.23 ± 39.64; 18.72 ± 14.95, respectively; p = 0.001). Serum albumin concentration was significantly lower in the MHCII-group (2.59 g/dL, 95% CI 2.31-2.87) than in the MHCII+ group (3.06 g/dL, 95% CI 2.88-3.23; p = 0.009). CD34 expression showed significant correlations with cranial mediastinal mass, WHO clinical substage, and fever (p = 0.028, p = 0.041, and p = 0.047, respectively). MHCII expression was correlated with adverse reactions to chemotherapy, cranial mediastinal masses, and fever (p = 0.009, p = 0.023, and p < 0.001, respectively). No statistically significant differences in the survival period were observed for any of the phenotypic aberrancies. Conclusion: Aberrant lymphomas are common in dogs. Some clinical prognostic factors that significantly correlate with aberrant immunophenotypes have been identified and can be applied clinically.

Siewert-Kartagener's syndrome in a dog.

Siewert-Kartagener's syndrome, a type of primary ciliary dyskinesia, is a complex disease comprising situs inversus, rhinosinusitis, and bronchiectasis. Situs inversus totalis is a condition in which all organs in the thoracic and abdominal cavities are reversed. Furthermore, primary ciliary dyskinesia, an autosomal genetic disease, may coexist with situs inversus totalis. Reports on Siewert-Kartagener's syndrome in veterinary medicine are limited. We report a rare case of primary ciliary dyskinesia with Siewert-Kartagener's syndrome in a dog, concurrently infected with canine distemper virus and type-2 adenovirus. This case highlights that situs inversus totalis can cause primary ciliary dyskinesia, and concurrent infections are possible.

Fecal microbiome in dogs with lymphoid and nonlymphoid tumors.

BACKGROUND: The association of gut microbiota with cancer etiology and prognosis has been demonstrated in humans and rodents but has not been studied in dogs with different types of tumors. HYPOTHESIS/OBJECTIVES: To analyze microbiome composition according to tumor progression based on metastasis, recurrence, and therapeutic response in canine tumors. ANIMALS: Thirty-two client-owned dogs were divided into 3 groups: healthy (n = 9), with lymphoma (n = 12), with nonlymphoid tumors (n = 11). METHODS: Retrospective case series included animals were divided into subgroups according to the nature and severity of their tumors. Feces were screened for the 16S rRNA gene. RESULTS: Overall, alpha diversity was significantly reduced in dogs with tumors (n = 23; 12 lymphoid and 11 nonlymphoid) compared to healthy dogs (n = 9). Bacteroides had lower abundance in canine tumors at genus level. Staphylococcus showed significantly reduced abundance in dogs with aggressive tumor progression. Higher white blood cell (WBC) and neutrophil counts and lower hematocrit were significant in dogs with aggressive tumor. Spearman's rank correlation coefficient analysis revealed several measurements that showed moderate to strong correlations, including Coprococcus with total WBC count, neutrophil count, and hematocrit in the aggressive tumor group, and Saccharimonas with serum albumin and sodium concentration in all tumor dogs. CONCLUSION AND CLINICAL IMPORTANCE: The diversity of the gut microbiome was significantly reduced in dogs with tumors compared to healthy dogs. Correlations were found between changes in blood measurements and changes in microbiome composition in relation to paraneoplastic syndrome.

Mott Cell Differentiation in Canine Multicentric B Cell Lymphoma with Cross-Lineage Rearrangement and Lineage Infidelity in a Dog.

Lymphoma is a severe condition characterized by the proliferation of neoplastic lymphoid cells. A 4-year-old female mongrel dog presented with solitary lymph node enlargement. Significant right prescapular lymphadenopathy and abdominal enlargement were observed during physical examination. A complete blood count revealed lymphocytosis, and a peripheral blood smear revealed lymphoblastosis and Mott cells. Fine needle aspiration cytology (FNAC) of the right prescapular lymph node revealed a predominant population of lymphoblasts and Mott cells. Based on the FNAC and blood smear results, the patient was diagnosed with leukemic state multicentric B-cell lymphoma with Mott cell differentiation. Subsequent PCR for antigen receptor rearrangement and flow cytometry revealed that the patient exhibited cross-lineage rearrangement (CLRA) and lineage infidelity (LI), respectively. CHOP-based chemotherapy was initiated, however, the patient's disease was progressive. The patient died three months after the initial presentation. Mott cell differentiation in canine B-cell lymphoma (MCL) has rarely been reported in the veterinary literature and seems to show an unusual clinical course. To the best of our knowledge, no reports of MCL with CLRA and LI exist. We report the clinical features, diagnosis, and treatment of MCL with CLRA and LI.

Two Clinical Cases of Feline Hemoplasmosis in Korea.

Feline hemotropic mycoplasmosis (hemoplasmosis) is an infection of the red blood cells caused by the Mycoplasma haemofelis (Mhf), Candidatus Mycoplasma haemominutum (CMhm), and Candidatus Mycoplasma turicensis (CMt). The existence of Mhf, CMhm, and CMt has been demonstrated in feral cats in Korea using molecular methods, but no clinical cases have yet been reported. This study reports 2 clinical cases of hemotropic mycoplasmosis caused by CMhm and CMt in 2 anemic cats. The first case was a client-owned intact female domestic shorthair cat that presented with fever, pale mucous membranes, and normocytic normochromic non-regenerative anemia. Prior to referral, an immunosuppressive prednisolone dose was administered at the local veterinary clinic for 1 month. The cat was diagnosed with high-grade alimentary lymphoma. Organisms were found on the surface of the red blood cells on blood smear examination. The second case was of a rescued cat that presented with dehydration and fever. The cat had normocytic normochromic non-regenerative anemia. Necropsy revealed concurrent feline infectious peritonitis. Polymerase chain reaction assay targeting 16S rRNA revealed CMhm infection in case 1 and dual infection of CMhm and CMt in case 2. Normocytic normochromic non-regenerative anemia was observed in both cats before and during the management of the systemic inflammation. This is the first clinical case report in Korea to demonstrate CMhm and CMt infections in symptomatic cats.

A case of leukaemia cutis in a dog with T-cell chronic lymphocytic leukaemia.

Leukaemia cutis (LC) is the infiltration of neoplastic leukocytes into the skin, characterised by haemorrhagic papules, nodules, and plaques. LC has been reported in human leukaemia patients, but it is extremely rare in dogs. A 13-year-old spayed female Golden Retriever that was previously diagnosed with chronic lymphocytic leukaemia was managed with chlorambucil (20 mg/m2 orally, every 2 weeks) and prednisolone (2 mg/kg orally, every other day) for 8 months; however, immunosuppression was temporarily discontinued because of a bacterial urinary tract infection. Cutaneous signs, including multifocal ecchymosis and white plaques, appeared 1 month after cessation of chemotherapy. Histopathological examination revealed small- to intermediate-sized lymphocytes with mild atypia in a perivascular to interstitial pattern within the superficial dermis. The bands of atypical cells within the superficial dermis were strongly and extensively positive for CD3 on immunohistochemistry. Polymerase chain reaction analysis of the biopsied skin revealed clonal rearrangement of the T-cell receptor gamma locus gene. Given the evidence of clinical signs, peripheral immunophenotyping, histopathology, immunohistochemistry, and clonal gene arrangement, LC was diagnosed. The lesions disappeared when chemotherapy was restarted but were occasionally observed when chemotherapy was stopped. To the authors' best knowledge, this is the first case report of LC in a dog.

Cell-Free DNA as a Diagnostic and Prognostic Biomarker in Dogs With Tumors.

Cell-free DNA (cfDNA) is derived from apoptosis/necrosis, active cellular secretion, and lysis of circulating cancer cells or micrometastases. In humans, cfDNA is widely used in cancer diagnosis, but veterinary research has yet to be actively conducted to establish it as a cancer biomarker. This retrospective study analyzed cfDNA levels in samples collected from dogs with neoplastic disease (n = 38), clinically ill dogs without neoplasia (n = 47), and healthy dogs (n = 35). cfDNA levels and clinical data were compared among groups, and prognostic analyses were performed within the neoplastic group. Furthermore, continual cfDNA measurements were performed during the chemotherapy of six dogs with lymphoma. Dogs with neoplasia showed significantly higher cfDNA concentrations than dogs without neoplasm, and the cfDNA oncentration in the lymphoid neoplasia group was significantly elevated among all neoplastic groups. Dogs with neoplasia and a plasma cfDNA concentration above 1,247.5 µg/L had shorter survival rates than those with levels below this threshold (26.5 vs. 86.1%, respectively, P < 0.05). In cases with complete remission in response to chemotherapy, the cfDNA concentration was significantly decreased compared with the first visit, whereas the cfDNA concentration was increased in cases with disease progression or death. Interestingly, a significant correlation was found between lymph node diameter and cfDNA concentration in dogs with multicentric lymphoma (R 2 = 0.26, P < 0.01). These data suggest that changes in cfDNA concentration could be used as a diagnostic biomarker for canine neoplasia. Furthermore, increased plasma DNA levels might be associated with shorter survival time, and cfDNA concentrations may reflect the response to chemotherapy.

Safety and immunological effects of recombinant canine IL-15 in dogs.

Interleukin-15 (IL-15) is a pleiotropic cytokine that plays pivotal roles in innate and adaptive immunity. It is also a promising cytokine for treating cancer. Despite growing interest in its use as an immunotherapeutic, its safety and immunological effects in dogs have not been reported. In this study, healthy dogs were given recombinant canine IL-15 (rcIL-15) intravenously at a daily dose of 20 µg/kg for 8 days and monitored for 32 days to determine the safety and immunological effects of rcIL-15. The repeated administration of rcIL-15 was well tolerated, did not cause any serious side effects, and promoted the selective proliferation and activation of canine anti-cancer effector cells, including CD3+CD8+ cytotoxic T lymphocytes, CD3+CD5dimCD21-, and non-B/non-T NK cell populations, without stimulating Treg lymphocytes. The rcIL-15 injections also stimulated the expression of molecules and transcription factors associated with the activation and effector functions of NK cells, including CD16, NKG2D, NKp30, NKp44, NKp46, perforin, granzyme B, Ly49, T-bet, and Eomes. These results suggest that rcIL-15 might be a valuable therapeutic adjuvant to improve immunity against cancer in dogs.

Radiography and ct features of atherosclerosis in two miniature schnauzer dogs.

Two miniature Schnauzer dogs with chronic pancreatitis were investigated. Both dogs showed systemic hypertension and increased concentrations of triglycerides and C-reactive protein. Abdominal radiography revealed cylindrical calcification in the retroperitoneum, and computed tomography (CT) showed extensive calcification of the abdominal and peripheral arteries in both dogs. Metastases and other dystrophic conditions that can cause arterial calcification were excluded based on the laboratory tests, and the dogs were diagnosed with atherosclerosis ante mortem. Atherosclerosis should be considered when extensive arterial calcification is observed on abdominal radiography or CT in miniature Schnauzers.

Primary Retrobulbar Leiomyosarcoma in a Dog: A Case Report.

A 2-year-old female Mongrel dog weighing 3.12 kg presented with a 2-month history of progressive exophthalmos of the left eye and periorbital swelling. Fine-needle aspiration cytology of the affected tissue revealed atypical cells of suspected malignant mesenchymal tumor origin. Computed tomography and magnetic resonance imaging revealed an ill-demarcated soft tissue mass in the left retrobulbar space extending into the nasal cavity and into the frontal lobes of the brain with destruction of the adjacent cribriform plate and the basisphenoid bone. Histopathological features of the tumor were consistent with the diagnosis of undifferentiated sarcoma. The tumor cells were immunoreactive for vimentin, smooth muscle actin, and desmin and negative for S100. These findings were mostly consistent with leiomyosarcoma arising from the smooth muscle on the retrobulbar tissues. Primary retrobulbar leiomyosarcoma is an extremely rare tumor in dogs. To expand our knowledge of retrobulbar leiomyosarcoma in dogs, we have described its clinical, diagnostic imaging, histopathological, and immunohistochemical characteristics in a dog.

Evaluation of treatment with a combination of mycophenolate mofetil and prednisolone in dogs with meningoencephalomyelitis of unknown etiology: a retrospective study of 86 cases (2009-2017).

BACKGROUND: Combination therapy with glucocorticoids and adjunctive immunomodulating drugs has been generally accepted as a standard treatment regimen for meningoencephalomyelitis of unknown etiology (MUE). We hypothesized that treatment with MMF as an adjunctive agent along with glucocorticoids would be effective and well-tolerated protocol in dogs with MUE. Eighty-six dogs with MUE between May 2009 and June 2017 were included (59 females and 27 males; mean age of 5.93 years; mean body weight of 3.83 kg). The medical records of dogs with MUE treated with prednisolone and MMF were retrospectively evaluated to determine the therapeutic response, survival time, and treatment-related adverse effects. RESULTS: A partial or complete response (CR) was recorded for 75 dogs. The overall median survival time from the initiation of treatment was 558 days. Dogs that showed CR with no relapse over the treatment period (from diagnosis to death) had significantly longer median survival times. A significantly higher mortality hazard ratio of 4.546 was recorded in dogs that failed to achieve CR. The interval between the onset of clinical signs and the clinical presentation was not significantly associated with CR, relapse rate, and survival time. Adverse effects included gastrointestinal upsets in 26 dogs (30.23%), sporadic infections in 17 dogs (19.77%), and pancreatitis in seven dogs (8.14%). CONCLUSIONS: The results suggest that adjunctive MMF treatment for MUE is safe and comparable to other immunosuppressive protocols. The treatment should focus on the achievement of CR and preventing relapse for successful management.

Expression of platelet-derived growth factor receptor-α/ß, vascular endothelial growth factor receptor-2, c-Abl, and c-Kit in canine granulomatous meningoencephalitis and necrotizing encephalitis.

BACKGROUND: Given the active research on targeted therapy using tyrosine kinase (TK) inhibitors (TKIs) in the field of oncology, further studies have recently been conducted to evaluate their use in autoimmune disorders. Based on immunological investigations, previous studies have suggested that granulomatous meningoencephalomyelitis (GME) and necrotizing encephalomyelitis (NE) are similar to multiple sclerosis (MS), which is a human autoimmune demyelinating central nervous system disease. OBJECTIVES: Considering this perspective, we hypothesized that canine GME and NE have significant expression of one or more TKs, which are associated with human MS pathogenesis. METHODS: To determine the possible use of conventional multi-targeted TKIs as a treatment for canine GME and NE, we characterized the immunohistochemical expression of platelet-derived growth factor receptor (PDGFR)-α, PDGFR-ß, vascular endothelial growth factor receptor (VEGFR)-2, c-Abl and c-Kit in GME and NE samples. RESULTS: Histological samples from four dogs with GME and three with NE were retrieved. All samples stained positive for PDGFR-ß (7/7 [100%]). PDGFR-α and c-Kit were expressed in 3/7 (42.8%) samples each. c-Abl was identified in 2/7 (28.5%) samples; no sample showed VEGFR-2 (0%) expression. Co-expression of TKs was identified in 6/7 (85.7%) dogs. CONCLUSIONS: All samples were positive for at least one or more of PDGFR-α, PDGFR-ß, c-Kit and c-Abl, which are known as the target TKs of conventional multi-targeted TKIs. Their presence does suggest that these TKs may play a role in the pathogenesis of GME and NE. Therefore, multi-targeted TKIs may provide benefits in the treatment of canine GME and NE by suppressing the activity of these TKs.

Canine adrenocorticotropic hormone-producing sinusoidal neuroendocrine tumor associated with Cushing's disease.

An 18-year-old male Yorkshire Terrier was admitted with a history of neurological signs including dullness and progressive tetraparesis. Physical examination revealed bilaterally symmetrical alopecia and pot-bellied abdomen. Computed tomography and necropsy examination showed a mass across the frontal sinus and cerebral frontal lobe, bilateral adrenocortical hyperplasia, and hepatomegaly. Histopathologically, the tumor lesions consisted of sheets, nests, or cords of small- to medium-sized round-to-polyhedral cells. Adrenal cortex showed bilateral diffuse cellular proliferation, and some hepatocytes showed intracytoplasmic glycogen accumulation. Immunohistochemically, the tumor cells were positive for pancytokeratin, chromogranin-A, neuron-specific enolase, S100, synaptophysin, and thyroid transcription factor-1 but negative for microtubule-associated proein-2 and neurofilament, leading to the diagnosis of neuroendocrine tumor. These tumor cells were also positive for adrenocorticotropic hormone.

Canine non-B, non-T NK lymphocytes have a potential antibody-dependent cellular cytotoxicity function against antibody-coated tumor cells.

BACKGROUND: The antibody-dependent cellular cytotoxicity (ADCC) is a cell-mediated immune defense mechanism in which effector immune cells actively lyse antibody-coated target cells. The ADCC of tumor cells is employed in the treatment of various cancers overexpressing unique antigens, and only natural killer (NK) cells are known to be major effectors of antibody mediated ADCC activity. Canine NK cells are still defined as non-B, non-T large granular lymphocytes because of the lack of information regarding the NK cell-restricted specific marker in dogs, and it has never been demonstrated that canine NK cells have ADCC ability against tumor cells. In the present study, we investigated whether canine non-B, non-T NK cells have ADCC ability against target antibody-coated tumor cells, using cetuximab and trastuzumab, the only human antibodies reported binding to canine cancer cells. RESULTS: Activated canine non-B, non-T NK cells (CD3-CD21-CD5-TCRαß-TCRγδ-) for 13~17 days ex vivo showed ADCC ability against trastuzumab- or cetuximab-coated target tumor cells expressing various levels of human epidermal growth factor receptor 2 (HER-2) and epidermal growth factor receptor (EGFR). Trastuzumab and cetuximab induced significant ADCC responses of canine NK cells even in CMT-U334 and CF41.Mg cells expressing low levels of HER-2 and/or EGFR, as well as in SKBR3 and DU145 cells overexpressing HER-2 and/or EGFR. The trastuzumab-mediated ADCC activity of NK cells was significantly enhanced by treatment with rcIL-21. CONCLUSIONS: The results of this study suggest that canine non-B, non-T NK lymphocytes have a potential ADCC function and that combinational strategies of monoclonal antibodies with either cytokines, which activate NK cells in vivo, or adoptive transfer of NK cells may be a feasible method for amplifying the efficacy of immunotherapy against malignant cancers even with very low expression of target molecules in dogs.

Effects of irradiation and leukoreduction on down-regulation of CXCL-8 and storage lesion in stored canine whole blood.

White blood cells (WBCs) and storage period are the main factors of transfusion reactions. In the present study, cytokine/chemokine concentrations after leukoreduction (LR) and irradiation (IR) in stored canine whole blood were measured. Red blood cell storage lesion caused by IR and LR were also compared. Blood samples from 10 healthy Beagles were divided into four groups (no treatment, LR-, IR-, and LR + IR-treated). Leukocytes were removed by filtration in the LR group and gamma radiation (25 Gy) was applied in the IR group. Immunologic factors (WBCs, interleukin-6 [IL-6], C-X-C motif chemokine ligand 8 [CXCL-8], and tumor necrosis factor-alpha) and storage lesion factors (blood pH, potassium, and hemolysis) were evaluated on storage days 0, 7, 14, 21, and 28. Compared to the treated groups, IL-6 and CXCL-8 concentrations during storage were significantly higher in the control (no treatment) group. LR did not show changes in cytokine/chemokine concentrations, and storage lesion presence was relatively mild. IR significantly increased CXCL-8 after 14 days of storage, but IR of leukoreduced blood did not increase CXCL-8 during 28 days of storage. Storage lesions such as hemolysis, increased potassium, and low pH were observed 7 days after IR and storage of blood, regardless of LR. IR of leukoreduced blood is beneficial to avoid immune reactions; however, storage lesions should be considered upon storage.

Molecular Identification of Sarcocystis grueneri in Wild Korean Water Deer (Hydropotes inermis argyropus).

The cysts of Sarcocystis grueneri were detected and characterized from the cardiac muscles of the Korean water deer (Hydropotes inermis argyropus). Of the 38 heart muscle samples examined by light microscopy, 10 were found infected with the cysts of Sarcocystis sp. The cysts appeared oval to spherical shape and measured 110-380 µm in length and 90-170 µm in width. A phylogenetic tree of the 18S rRNA sequences (1.5 kb) revealed a close relationship of the infected cysts to genus Sarcocystis. The 18S rRNA sequence of the infected cysts showed 100% identity to S. grueneri and 97% to S. capracanis. Here, we first report the S. grueneri infections in the Korean water deer.

Comparison of Phenotypic and Functional Characteristics Between Canine Non-B, Non-T Natural Killer Lymphocytes and CD3+CD5dimCD21- Cytotoxic Large Granular Lymphocytes.

Natural killer (NK) cells play a pivotal role in the immune response against infections and malignant transformation, and adopted transfer of NK cells is thought to be a promising therapeutic approach for cancer patients. Previous reports describing the phenotypic features of canine NK cells have produced inconsistent results. Canine NK cells are still defined as non-B and non-T (CD3-CD21-) large granular lymphocytes. However, a few reports have demonstrated that canine NK cells share the phenotypic characteristics of T lymphocytes, and that CD3+CD5dimCD21- lymphocytes are putative canine NK cells. Based on our previous reports, we hypothesized that phenotypic modulation could occur between these two populations during activation. In this study, we investigated the phenotypic and functional differences between CD3+CD5dimCD21- (cytotoxic large granular lymphocytes) and CD3-CD5-CD21- NK lymphocytes before and after culture of peripheral blood mononuclear cells isolated from normal dogs. The results of this study show that CD3+CD5dimCD21- lymphocytes can be differentiated into non-B, non-T NK (CD3-CD5-CD21-TCRαß-TCRγδ-GranzymeB+) lymphocytes through phenotypic modulation in response to cytokine stimulation. In vitro studies of purified CD3+CD5dimCD21- cells showed that CD3-CD5-CD21- cells are derived from CD3+CD5dimCD21- cells through phenotypic modulation. CD3+CD5dimCD21- cells share more NK cell functional characteristics compared with CD3-CD5-CD21- cells, including the expression of T-box transcription factors (Eomes, T-bet), the production of granzyme B and interferon-γ, and the expression of NK cell-related molecular receptors such as NKG2D and NKp30. In conclusion, the results of this study suggest that CD3+CD5dimCD21- and CD3-CD5-CD21- cells both contain a subset of putative NK cells, and the difference between the two populations may be due to the degree of maturation.

Diagnosis of Lymphoid Malignancy by PCR for Analysis of Antigen Receptor Rearrangement after Blood Transfusion in a Dog with Acute Lymphocytic Leukemia.

Acute lymphocytic leukemia (ALL) is uncommon lymphoid malignancy in dogs, and its diagnosis is challenging. A 14-year-old spayed female mixed breed dog was transferred to a veterinary medical teaching hospital for an immediate blood transfusion. The dog showed lethargy, pale mucous membranes, and a weak femoral pulse. Complete blood count revealed non-regenerative anemia and severe leukopenia with thrombocytopenia. ALL was tentatively diagnosed based on the predominance of immature lymphoblasts on blood film examination. For confirmation of lymphoid malignancy, PCR for antigen receptor rearrangement (PARR) on a peripheral blood sample and flow cytometry analysis were performed after blood transfusion. Flow cytometry analysis revealed that lymphocyte subsets were of normal composition, but PARR detected a T-cell malignancy. The dog was diagnosed with ALL and survived 1 wk after diagnosis. In conclusion, after blood transfusion, flow cytometry was not a reliable diagnostic method for an ALL dog, whereas PARR could detect lymphoid malignancy. Our results suggest that PARR should be the first-line diagnostic tool to detect canine lymphoid malignancy after a blood transfusion.

Changes in gene expression of tumor necrosis factor alpha and interleukin 6 in a canine model of caerulein-induced pancreatitis.

Acute pancreatitis is an inflammatory process that frequently involves peripancreatic tissues and remote organ systems. It has high morbidity and mortality rates in both human and veterinary patients. The severity of pancreatitis is generally determined by events that occur after acinar cell injury in the pancreas, resulting in elevated levels of various proinflammatory mediators, such as interleukin (IL) 1ß and 6, as well as tumor necrosis factor alpha (TNF-α). When these mediators are excessively released into the systemic circulation, severe pancreatitis occurs with systemic complications. This pathophysiological process is similar to that of sepsis; thus, there are many striking clinical similarities between patients with septic shock and those with severe acute pancreatitis. We induced acute pancreatitis using caerulein in dogs and measured the change in the gene expression of proinflammatory cytokines. The levels of TNF-α and IL-6 mRNA peaked at 3 h, at twice the baseline levels, and the serum concentrations of amylase and lipase also increased. Histopathological examination revealed severe hyperemia of the pancreas and hyperemia in the duodenal villi and the hepatic sinusoid. Thus, pancreatitis can be considered an appropriate model to better understand the development of naturally occurring sepsis and to assist in the effective treatment and management of septic patients.

La pancréatite aigüe est un processus inflammatoire qui implique fréquemment les tissus péri-pancréatiques et des systèmes organiques éloignés. Elle a des taux de morbidité et de mortalité élevés autant chez les humains que chez les animaux. La sévérité de la pancréatite est généralement déterminée par des évènements qui se produisent suite à des dommages aux cellules acinaires dans le pancréas, et qui induisent des niveaux élevés de différents médiateurs pro-inflammatoires, tels que l'interleukine (IL) 1ß et 6, ainsi que le facteur nécrosant des tumeurs alpha (TNFα). Lorsque ces médiateurs sont libérés de manière excessive dans la circulation systémique, une pancréatite sévère se produit avec des complications systémiques. Ce processus pathophysiologique est similaire à celui d'un sepsis; donc, il y a plusieurs similarités cliniques entre des patients avec un choc septique et ceux avec une pancréatite aigüe sévère. Nous avons induit une pancréatite aigüe en utilisant de la caeruléine chez des chiens et avons mesuré le changement dans l'expression des gènes des cytokines pro-inflammatoires. Les niveaux d'ARNm de TNFα et d'IL-6 ont culminé après 3 h, atteignant le double des niveaux de base, et les concentrations sériques d'amylase et de lipase augmentèrent également. Un examen histopathologique a révélé une hyperémie sévère du pancréas et une hyperémie dans les villosités duodénales et les sinusoïdes hépatiques. Ainsi, la pancréatite peut être considérée un modèle approprié pour mieux comprendre le développement d'un sepsis naturel et aider dans le traitement efficace et la gestion de patients septiques.(Traduit par Docteur Serge Messier).

Valproic acid attenuates the expression of pro-inflammatory cytokines lipopolysaccharide-treated canine peripheral blood mononuclear cells (in vitro) and in a canine endotoxemia model (in vivo).

Valproic acid (VPA), a known histone deacetylase inhibitor, has been used as an anticonvulsant in dogs. VPA also has anti-inflammatory properties, but there are no reports on the immunomodulatory effects of VPA in canine endotoxemia. In the present study, we demonstrate that the use of VPA significantly reduces the production of early-phase pro-inflammatory cytokines (TNF-α, IL-6) caused by lipopolysaccharide (LPS) stimulation both in vitro and in vivo. For the in vitro study, VPA was evaluated for 24h on LPS (100 ng/ml)-treated canine peripheral blood mononuclear cells (PBMCs) which isolated from 5 healthy Beagle dogs. VPA significantly decreased the mRNA expression of TNF-α and IL-6 in a dose-dependent manner (p<0.05 for IL-6; p<0.01 for TNF-α). Fourteen adult Beagles were studied for in vivo study; nine dogs received a low dose of LPS (10 µg/kg/h) via continuous IV infusion for 12h to induce endotoxemia whereas 5 dogs received normal saline as controls. Four out of 9 endotoxemic dogs were administered VPA (50mg/kg, IV) at 1h and 12h along with the LPS infusion. Three hours after the first administration of VPA, IL-6 mRNA expressions in PBMCs significantly decreased (p=0.033 vs. LPS group). VPA also significantly decreased the circulating TNF-α (p=0.044 vs. LPS group at 3h) and IL-6 protein at 3h (p=0.034 vs. LPS group) and 6h (p=0.026 vs. LPS group) post-treatment. Our study suggests that VPA attenuates the expression of pro-inflammatory cytokines in a canine endotoxemia model in vitro and in vivo. We speculate that valproic acid may be useful for reducing inflammatory cytokine levels in dogs with sepsis.