Inhibition of Myeloperoxidase Pro-Fibrotic Effect by Noscapine in Equine Endometrium.

Myeloperoxidase is an enzyme released by neutrophils when neutrophil extracellular traps (NETs) are formed. Besides myeloperoxidase activity against pathogens, it was also linked to many diseases, including inflammatory and fibrotic ones. Endometrosis is a fibrotic disease of the mare endometrium, with a large impact on their fertility, where myeloperoxidase was shown to induce fibrosis. Noscapine is an alkaloid with a low toxicity, that has been studied as an anti-cancer drug, and more recently as an anti-fibrotic molecule. This work aims to evaluate noscapine inhibition of collagen type 1 (COL1) induced by myeloperoxidase in equine endometrial explants from follicular and mid-luteal phases, at 24 and 48 h of treatment. The transcription of collagen type 1 alpha 2 chain (COL1A2), and COL1 protein relative abundance were evaluated by qPCR and Western blot, respectively. The treatment with myeloperoxidase increased COL1A2 mRNA transcription and COL1 protein, whereas noscapine was able to reduce this effect with respect to COL1A2 mRNA transcription, in a time/estrous cycle phase-dependent manner (in explants from the follicular phase, at 24 h of treatment). Our study indicates that noscapine is a promising drug to be considered as an anti-fibrotic molecule to prevent endometrosis development, making noscapine a strong candidate to be applied in future endometrosis therapies.

CT findings in a dog with subacute myopathy and later fibrotic contracture of the infraspinatus muscle.

A 5-year-old Norwegian elkhound was referred due to an acute onset of lameness and persistent shoulder pain over a period of 3 weeks. Computed tomography demonstrated an enlarged, hypoattenuating right infraspinatus muscle with peripheral contrast enhancement and a nonenhancing center, without concurrent lesions in superficial structures or bones. The right infraspinatus muscle showed progressive atrophy on consecutive CT studies. The dog developed clinical symptoms compatible with fibrotic infraspinatus contracture 2 months after the initial presentation, and was treated with infraspinatus tenotomy. Histopathological diagnoses based on intraoperative biopsy samples were fibrotic muscle atrophy and muscle hypertrophy with regeneration.

EFFECTS OF DOXYCYCLINE HYCLATE, ONE PERCENT POLIDOCANOL, AND ABSOLUTE ETHANOL ON THE CUTANEOUS AND SUBCUTANEOUS TISSUES OF CHICKENS (GALLUS GALLUS DOMESTICUS) AND THE POTENTIAL IMPLICATIONS IN TREATING CERVICOCEPHALIC DIVERTICULA RUPTURE.

The objective of this pilot study was to examine the histologic effects associated with three known sclerosing agents and their ability to induce fibrosis in the subcutaneous space between the cervicocephalic air sac and skin. In the future, these drugs may prove useful in treating birds experiencing cervicocephalic diverticula rupture. The agents used were 1% polidocanol, absolute ethanol, and doxycycline hyclate. Twelve healthy adult chickens (Gallus gallus domesticus) were used in this study. The chickens were randomly allocated into three groups denoting day of euthanasia (day 4, 7, or 14). On day 0, all agents were injected (0.2 ml) subcutaneously, in a four-point grid fashion, in both the cervical and pectoral region of each bird. After euthanasia, the skin and subcutaneous tissues corresponding to the injection sites were harvested for histologic assessment. Tissue sections were assessed for fibrosis and lymphocytic and histiocytic inflammation. A scoring system was established to rank sclerosing agents by fibrosing and inflammatory ability. In the cervical region of chickens, 1% polidocanol induced the greatest inflammatory changes by day 7. Data suggest that doxycycline hyclate may produce the greatest cutaneous and subcutaneous fibrosis overall among all groups of birds. No adverse reactions were associated with any injection. Sterile saline produced the least amount of inflammation when assessed with the scoring system. Further investigation is needed to determine the safety of injections of larger volume with these chemicals and whether these findings can be extrapolated to birds with disease.

Myocardial Changes in Diabetic and Nondiabetic Nonhuman Primates.

Diabetic human patients have increased risk of heart failure compared to healthy subjects. The underlying mechanisms for this are not fully understood, and to help develop improved treatment strategies, well-characterized animal models are essential. To investigate cardiac dysfunction in diabetes, this study evaluated myocardial changes in 10 aging rhesus monkeys with and without diabetes. Based on evaluation of plasma glycosylated hemoglobin and glucose, 7 of 10 rhesus macaques had diabetes for a minimum of 11 months, while 3 of 10 were categorized as nondiabetic. A detailed histological examination of formalin-fixed left ventricular myocardial samples was followed by a semiquantitative evaluation of myocardial fibrosis and fat infiltration; digital quantifications of myocardial collagen, lipofuscin, and nuclear area fractions; and measurements of cardiomyocyte diameter. Histological myocardial evaluation revealed the presence of lipofuscin; large nuclei; interstitial, replacement, and vascular fibrosis; adipocyte infiltration; and vacuolar degeneration with atrophy of cardiomyocytes and fibrosis. However, there were no differences between groups for semiquantitative fat infiltration, fibrosis, cardiomyocyte size, collagen, or nuclear and lipofuscin area fraction. Lipofuscin area fraction correlated with plasma insulin, triglyceride, total cholesterol, and high-density lipoprotein cholesterol concentrations. In conclusion, myocardial pathological changes were found in left ventricular myocardium in aged rhesus macaques, independent of the stage of diabetes. The duration of diabetes might have been too short to cause differences between groups.

Idiopathic Myocardial Fibrosis in Captive Chimpanzees (Pan troglodytes).

Cardiovascular disorders and predominantly idiopathic myocardial fibrosis are frequently associated with mortality among zoo-housed chimpanzees (Pan troglodytes). Formalin-fixed whole hearts of deceased chimpanzees housed in zoos (n = 33) and an African sanctuary (n = 2) underwent detailed macroscopic and histopathologic examination using a standardized protocol. Archived histological slides from the hearts of 23 additional African sanctuary-housed chimpanzees were also examined. Myocardial fibrosis (MF) was identified in 30 of 33 (91%) of the zoo-housed chimpanzees but none of the 25 sanctuary-housed chimpanzees. MF was shown to be characterized by both interstitial and replacement fibrosis. Immunophenotyping demonstrated that the fibrotic lesions were accompanied by the increased presence of macrophages, alpha smooth muscle actin-positive myofibroblasts, and a minimal to mild T-cell-dominant leukocyte infiltration. There was no convincing evidence of cardiotropic viral infection or suggestion that diabetes mellitus or vitamin E or selenium deficiency were associated with the presence of the lesion. However, serum vitamin D concentrations among zoo-housed chimpanzees were found to be lower in seasons of low ultraviolet light levels.

Fatal pulmonary hemorrhage in a horse during bronchoalveolar lavage - single case report.

BACKGROUND: Pulmonary hemorrhage is a rare cause of death in horses. Hemorrhage within the respiratory tract has many causes, including mycosis of the guttural pouch, invasive procedures causing serious trauma to nasal conchae, or lung biopsy. We report on a rare case of a fatal pulmonary hemorrhage in a horse after a severe cough during bronchoalveolar lavage. To the best of our knowledge, this is the first report of spontaneous hemorrhage in a horse during bronchoalveolar lavage. CASE PRESENTATION: A 21-year-old mare which belonged to the didactic herd of The Faculty of Veterinary Medicine underwent BAL procedure for training purposes. Clinical examination prior to the procedure did not reveal any abnormalities and the horse had been classified as healthy. The horse was sedated with 0.01 mg/kg of detomidine and 0.01 mg/kg of butorphanol. The silicon BAL catheter was passed through the nasal passage into the trachea and then into the bronchus. Before catheter was wedged, the mare began to cough heavily and massive haemorrhage from mouth and nostrils occurred. Despite fluid therapy, shock occurred within 15 min and the mare was euthanized. Upon necropsy, site of hemorrhage was identified in the left lobar caudal bronchi, from a large blood vessel running directly beneath the bronchial wall. Upon histology, a chronic lympho-plasmocytic inflammatory process in left bronchi was identified. Moreover, Masson's trichrome staining revealed severe, perivascular fibrosis. CONCLUSION: Although BAL is a relatively safe procedure, and such complications should be treated as extremely rare, this case indicates that, in some individuals with specific subclinical problems, even mild physical force such as a cough can lead to rupture of the artery.

The Causes of Canine Myocarditis and Myocardial Fibrosis Are Elusive by Targeted Molecular Testing: Retrospective Analysis and Literature Review.

Myocarditis can cause death or permanent heart damage. As epidemiologic and etiopathologic data for canine myocarditis are lacking, we performed a retrospective study using nucleic acid extracted from archived (2007 to 2015) tissues from myocarditis cases and control dogs without myocardial lesions. Heart tissue from pediatric/juvenile and adult dogs was tested with a comprehensive panel of conventional and real-time polymerase chain reaction (PCR) assays targeting recognized agents of canine myocarditis based on a literature review and informed by the comparative epidemiology of human myocarditis. The PCR screen, which included canine parvovirus 2 (CPV-2), canine distemper virus, canine herpesvirus, Borrelia spp, West Nile virus, adenovirus, parainfluenza virus, pneumovirus, respiratory coronavirus, influenza virus, Bartonella spp, Rickettsia spp, Mycoplasma spp, and Neospora caninum, did not detect agents in 35 of 66 cases (53%; 95% confidence interval [CI], 41%-65%) and was frequently negative in adults (21/26); by comparison, agents were not detected in 27 of 57 controls (47%; 95% CI, 35%-60%). Canine distemper virus, herpesvirus, adenovirus, coronavirus, parainfluenza virus, Mycoplasma haemocanis, and N. caninum were occasionally detected in both cases and controls; thus, PCR detection was not considered to indicate causation. We previously reported that CPV-2 continues to be associated with myocarditis in young dogs despite widespread vaccination; in adults, CPV-2 was detected in 2 of 26 cases and 4 of 22 controls. As several agents were similarly detected in cases and controls, it is unclear if these are cardiopathogenic, incidental, or latent. West Nile virus was detected at the analytic limit in 1 adult case. We did not detect Borrelia spp, Bartonella spp, Rickettsia spp, or influenza A virus in the myocarditis cases. These data demonstrate the limitations of current targeted diagnostic tests and the need for additional research to identify unknown agents and develop testing strategies for canine myocarditis.

Fat, Cartilage, and Bone Metaplasia in Lungs of Cattle With Caudal Pleural Lesions and Subjacent Interstitial Fibrosis.

The changes associated with condemned lungs in cattle with chronic pleural lesions of the caudal lobes were characterized by histology and immunohistochemistry (IHC). Fibroproliferative pleural lesions were microscopically confirmed. Occasionally, the pleural lesions also included adipose, chondroid, and osseous metaplasia that were covered by mesothelial cells, mostly in the absence of inflammation. Other lungs also showed fibrosis in the subpleural interstitium and interlobular septa. In both condemned and noncondemned lungs, immunoreactivity to Wilms tumor 1 (WT1) was normally observed on surface mesothelial cells but not on the submesothelial fibroblasts and myofibroblasts. Conversely, the myofibroblasts beneath the pleura, but not the mesothelial cells, showed immunoreactivity to alpha smooth muscle actin and calponin. However, in the lungs with myofibroblastic foci in the pleura, the proliferated cells maintained WT1 immunoreactivity similar to those of some metaplastic cells. These findings may reflect the plasticity of mesothelial cells in vivo.

Chronic Renal Changes After a Single Ischemic Event in an Experimental Model of Feline Chronic Kidney Disease.

Previous work demonstrated renal fibrosis 70 days after a single unilateral in vivo renal ischemic event, but changes associated with a single episode of renal ischemia past this time are unknown. In this study, we evaluated renal function and structural changes 6 months after a 90-minute in vivo unilateral renal ischemic event. Six adult female cats underwent unilateral renal ischemia and renal function was followed for 6 months, at which time the kidneys were evaluated by histology and histomorphometry. Over time, there was a significant reduction in the glomerular filtration rate and an elevation of serum creatinine of 31% and 42%, respectively. All cats had tubulointerstitial lesions characterized by segmental interstitial inflammation, tubular atrophy, and interstitial fibrosis. Unlike short-term studies, ischemic kidneys had variable numbers of obsolescent glomeruli, consistent with the development of atubular glomeruli and subsequent ischemic glomerulosclerosis. Chronic changes associated with acute renal ischemia may include loss of function and glomerulosclerosis.

Safety and efficacy of topically applied 0.5% and 1% pirfenidone in a canine model of subconjunctival fibrosis.

OBJECTIVE: To evaluate tissue levels, safety, and efficacy of topical ophthalmic 0.5% and 1% pirfenidone in decreasing subconjunctival fibrosis. ANIMAL STUDIED: Twelve normal beagle dogs PROCEDURES: A 5 × 1 mm diameter silicone disk was implanted subconjunctivally in one eye, and then dogs were treated with topical 0.5% pirfenidone (n = 9) in artificial tears or artificial tears alone (n = 3) for 28 days. To evaluate tissue drug levels, a single sample of tears, conjunctiva, and aqueous humor was collected 30 (n = 3), 90 (n = 3), and 180 min (n = 3) following administration of the last drop of pirfenidone, respectively. Fibrous capsule thickness and staining for Ki67 and fibroblast activation protein alpha (FAPα) were evaluated histologically. After a 2-week washout, the experiment was repeated in the opposite eye and using 1% pirfenidone. RESULTS: Treatment with pirfenidone resulted in thinner fibrous capsules and decreased staining for FAPα with no adverse effects. The implant in one dog treated with pirfenidone extruded. There was no difference in tissue levels, capsular thickness, or staining for Ki67 or FAPα between dogs treated with 0.5% or 1% pirfenidone. CONCLUSIONS: Pirfenidone may decrease fibrosis following glaucoma shunt surgery and can potentially be used indefinitely due to minimal side effects.

Ultrasonographic and histopathological features in 8 cats with fibrotic small intestinal stricture.

Benign stricture is an uncommon cause of chronic small intestinal obstruction in the cat. The purpose of this retrospective case series was to describe the ultrasonographic features, histopathological findings, and clinical presentation in a group of cats with benign small intestinal stricture. Inclusion criteria were cats presenting during the period 2010-2017, and that had ultrasonography and small intestinal stricture confirmed at surgery. For each cat, clinical data and ultrasonographic findings were retrieved from the medical record, and histopathology, where available, was reviewed. Eight cats met the inclusion criteria. The location of strictures was duodenum (1/8), mid- to distal jejunum (4/8), and ileum (3/8). Ultrasonographic findings included gastric distension (8/8) and generalized (3/8) or segmental (5/8) intestinal dilation consistent with mechanical obstruction. Ingesta did not propagate beyond the strictured segment. Wall thickening was mild to moderate (3-6 mm). Normal wall layering was disrupted in all cats. Strictures were predominantly hypoechoic (7/8) and associated with hyperechoic peri-intestinal mesentery (6/8). Annular strictures (5/8) were less than 15 mm in length whereas long-segment strictures (3/8) were greater than 15 mm in length. Histopathology showed transmural disease with fibrosis and inflammation (8/8), often (6/8) extending into the bordering mesentery. The mucosa was the most severely affected layer and epithelial injury accompanied the mucosal fibrosis/inflammation. Clinical presentation reflected delayed diagnosis of chronic bowel obstruction with debilitation (8/8), marked weight loss (8/8), and prerenal azotemia (5/8). Benign fibrostenotic stricture should be considered a differential diagnosis in debilitated young cats presenting with chronic bowel disease and ultrasonographic features of intestinal obstruction.

Altering equine corneal fibroblast differentiation through Smad gene transfer.

OBJECTIVE: To explore the impact of equine corneal fibroblast (ECF) to myofibroblast (ECM) differentiation by altering the expression of the Smad genes either individually or in combination. Specifically, we sought to examine the ECF differentiation after (a) silencing of Smad2, 3, and 4 profibrotic genes individually and (b) overexpression of antifibrotic Smad7 gene and in a combination with pro- and antifibrotic Smad genes. METHODS: Equine corneal fibroblast primary cultures were generated as previously described. ECFs were transfected with individual plasmids which silenced gene expression of either Smad2, 3, or 4 or in combination with a plasmid overexpressing Smad7 using Lipofectamine 2000™ or Lipofectamine BLOCK-iT™. Smad-transfected clones were then exposed to TGF-ß1 to induce differentiation to myofibroblasts. Immunofluorescence and qRT-PCR techniques quantified levels of ECF differentiation to ECM by measuring alpha smooth muscle actin, a known marker of ECM transdifferentiation. RESULTS: Silencing of individual Smad2, 3, or 4 genes or overexpression of Smad7 showed significant inhibition of ECF transdifferentiation (73-83% reduction). Silencing of Smad2 showed the greatest inhibition of ECF transdifferentiation in (a) and was therefore utilized for the combination gene transfer testing. The combination gene transfer consisting of Smad7 overexpression and Smad2 silencing attenuated ECF differentiation significantly; however, the level was not significant compared to the overexpression of Smad7 individually. CONCLUSIONS: Using gene transfer technology involving profibrotic Smad silencing, antifibrotic Smad overexpression or its combination is a novel strategy to control TGF-ß1-mediated fibrosis in equine fibroblasts. Combination gene therapy was not better than single gene therapy in this study.

TGF-ß1 promotes Staphylococcus aureus adhesion to and invasion into bovine mammary fibroblasts via the ERK pathway.

Fibroblasts are the structural base of mammary breast tissues. TGF-ß1 can regulate the fibrotic process; however, it remains unclear whether TGF-ß1 influences the susceptibility of fibroblasts to bacteria. Staphylococcus aureus (S. aureus) is a major bacterium in both chronic and subclinical mastitis in lactating cows that acts by invading host cells. To better understand the function of TGF-ß1 in bovine mammary fibroblasts' (BMFBs) susceptibility to bacteria as well as the mechanisms involved, a primary BMFB model was established by treating cells with TGF-ß1 followed by infection with S. aureus. The results revealed that the adhesion and invasion of S. aureus into BMFBs was significantly increased after cells were treated with 5 ng/ml TGF-ß1 for 12 h. Moreover, TGF-ß1 can increase Collagen I and α-SMA expression via activation of ERK signaling. However, the increased adhesion and invasion of S. aureus can be blocked by specific antibodies against either Collagen I or α-SMA, indicating that the increased adhesion and invasion are dependent on TGF-ß1-induced upregulation of both Collagen I and α-SMA. Using PD98059, an ERK inhibitor, could also decrease the adhesion and invasion of S. aureus. These results indicate that TGF-ß1 could promote S. aureus adhesion to and invasion into BMFBs by increasing Collagen I and α-SMA expression and may provide a novel target for controlling bovine mastitis.

Parvovirus Infection Is Associated With Myocarditis and Myocardial Fibrosis in Young Dogs.

Perinatal parvoviral infection causes necrotizing myocarditis in puppies, which results in acute high mortality or progressive cardiac injury. While widespread vaccination has dramatically curtailed the epidemic of canine parvoviral myocarditis, we hypothesized that canine parvovirus 2 (CPV-2) myocardial infection is an underrecognized cause of myocarditis, cardiac damage, and/or repair by fibrosis in young dogs. In this retrospective study, DNA was extracted from formalin-fixed, paraffin-embedded tissues from 40 cases and 41 control dogs under 2 years of age from 2007 to 2015. Cases had a diagnosis of myocardial necrosis, inflammation, or fibrosis, while age-matched controls lacked myocardial lesions. Conventional polymerase chain reaction (PCR) and sequencing targeting the VP1 to VP2 region detected CPV-2 in 12 of 40 cases (30%; 95% confidence interval [CI], 18%-45%) and 2 of 41 controls (5%; 95% CI, 0.1%-16%). Detection of CPV-2 DNA in the myocardium was significantly associated with myocardial lesions ( P = .003). Reverse transcription quantitative PCR amplifying VP2 identified viral messenger RNA in 12 of 12 PCR-positive cases and 2 of 2 controls. PCR results were confirmed by in situ hybridization, which identified parvoviral DNA in cardiomyocytes and occasionally macrophages of juvenile and young adult dogs (median age 61 days). Myocardial CPV-2 was identified in juveniles with minimal myocarditis and CPV-2 enteritis, which may indicate a longer window of cardiac susceptibility to myocarditis than previously reported. CPV-2 was also detected in dogs with severe myocardial fibrosis with in situ hybridization signal localized to cardiomyocytes, suggesting prior myocardial damage by CPV-2. Despite the frequency of vaccination, these findings suggest that CPV-2 remains an important cause of myocardial damage in dogs.

Shunt tube placement for amelioration of cerebrospinal fluid flow obstruction caused by spinal cord subarachnoid fibrosis in dogs.

OBJECTIVE: To describe a novel technique for ameliorating cerebrospinal fluid flow obstruction secondary to pia-arachnoid fibrosis in dogs and report outcome. STUDY DESIGN: Descriptive report and retrospective case series. ANIMALS: Dogs with cerebrospinal fluid (CSF) flow obstruction (n = 7). METHODS: Medical records were searched for dogs that had a subarachnoid-subarachnoid shunt placed for treatment of CSF flow obstruction. Data collected included age, sex, breed, clinical signs and duration of signs prior to examination, neurologic status and localization prior to surgery, pre-surgical diagnostics, surgical technique, histopathology, postoperative neurologic examination, time to discharge from hospital, and outcome. RESULTS: All dogs were diagnosed at surgery with a fibrotic adhesion between the arachnoid and pia mater. A subarachnoid shunting tube was implanted to allow CSF flow across the lesion site. Five dogs showed improvement of clinical signs, 3 of which showed complete recovery and 2 of which showed improvement without resolution of all clinical signs. Two dogs showed no change at 7 and 24 months postoperatively. CONCLUSION: Bridging a region of pia-arachnoid fibrosis with a tube placed in the subarachnoid space can ameliorate or prevent progression of associated clinical signs.

Mesoporous carbon nanomaterials induced pulmonary surfactant inhibition, cytotoxicity, inflammation and lung fibrosis.

Environmental exposure and health risk upon engineered nanomaterials are increasingly concerned. The family of mesoporous carbon nanomaterials (MCNs) is a rising star in nanotechnology for multidisciplinary research with versatile applications in electronics, energy and gas storage, and biomedicine. Meanwhile, there is mounting concern on their environmental health risks due to the growing production and usage of MCNs. The lung is the primary site for particle invasion under environmental exposure to nanomaterials. Here, we studied the comprehensive toxicological profile of MCNs in the lung under the scenario of moderate environmental exposure. It was found that at a low concentration of 10µg/mL MCNs induced biophysical inhibition of natural pulmonary surfactant. Moreover, MCNs at similar concentrations reduced viability of J774A.1 macrophages and lung epithelial A549 cells. Incubating with nature pulmonary surfactant effectively reduced the cytotoxicity of MCNs. Regarding the pro-inflammatory responses, MCNs activated macrophages in vitro, and stimulated lung inflammation in mice after inhalation exposure, associated with lung fibrosis. Moreover, we found that the size of MCNs played a significant role in regulating cytotoxicity and pro-inflammatory potential of this nanomaterial. In general, larger MCNs induced more pronounced cytotoxic and pro-inflammatory effects than their smaller counterparts. Our results provided valuable information on the toxicological profile and environmental health risks of MCNs, and suggested that fine-tuning the size of MCNs could be a practical precautionary design strategy to increase safety and biocompatibility of this nanomaterial.

TGF-ß1 promotes bovine mammary fibroblast proliferation through the ERK 1/2 signalling pathway.

The abnormal proliferation of bovine mammary fibroblasts (BMFBs) impairs mammary gland development and lactation. Severe manifestations develop into breast fibrosis, leading to the culling of cows and causing serious losses to the dairy industry. Transforming growth factor ß1 (TGF-ß1) is an important modulator of cell proliferation and extracellular matrix formation; however, limited information is available on BMFBs. In this study, a convenient and stable culture method for BMFBs was established. Treatment with 5 ng/mL of TGF-ß1 significantly promoted the proliferation of BMFBs and accelerated the cell cycle. TGF-ß1 stimulation for up to 12 h significantly increased the relative ERK1/2 mRNA expression and enhanced the protein expression of p-ERK1/2 and cyclin D1. Conversely, the ERK1/2 inhibitor PD98059 blocked these TGF-ß1 effects. Further exploration using a mouse model showed that TGF-ß1 significantly increased the proportion of fibroblasts and accelerating the cell transition from the G1 to G2/M phases. In addition, TGF-ß1 enhanced the expression of fibrosis markers, α-SMA and I Collagen, which could be blocked efficiently by the PD98059 in mouse mammary gland. Finally, immunofluorescence analysis confirmed that TGF-ß1 promoted fibroblast proliferation in healthy dairy cows after normal long-term dietary corn straw roughage supplementation. It is suggested that the diet may promote mammary fibroblast proliferation by raising the level of TGF-ß1. Our study provides new insights into how nutrition causes undesirable changes in mammary gland structure.

Characterization of a Cardiorenal-like Syndrome in Aged Chimpanzees (Pan troglodytes).

Cardiorenal syndrome involves disease and dysfunction of the heart that leads to progressive renal dysfunction. This study investigated the relationship between cardiac and renal disease in 91 aged chimpanzees at the Alamogordo Primate Facility by evaluation of the medical histories, metabolic parameters, functional measurements of the cardiovascular system, clinical pathology, and histopathology focused on the heart and kidney. Cardiac fibrosis was the most frequent microscopic finding in 82 of 91 animals (90%), followed by glomerulosclerosis with tubulointerstitial fibrosis in 63 of 91 (69%). Cardiac fibrosis with attendant glomerulosclerosis and tubulointerstitial fibrosis was observed in 58 of 91 animals (63%); there was a statistically significant association between the 2 conditions. As the severity of cardiac fibrosis increased, there was corresponding increase in severity of glomerulosclerosis with tubulointerstitial fibrosis. Altered metabolic, cardiovascular, and clinical pathology parameters indicative of heart and kidney failure were commonly associated with the moderate to severe microscopic changes, and concurrent heart and kidney failure were considered the cause of death. The constellation of findings in the chimpanzees were similar to cardiorenal syndrome in humans.

Unilateral Renal Ischemia as a Model of Acute Kidney Injury and Renal Fibrosis in Cats.

The objectives of this study were to define the acute and chronic effects of 1-hour unilateral in vivo renal ischemia on renal function and histology in cats. Twenty-one adult purpose-bred research cats were anesthetized, and 1 kidney underwent renal artery and vein occlusion for 1 hour. Serum creatinine and urea concentrations, urine protein:creatinine ratio, urine-specific gravity, glomerular filtration rate, hematocrit, platelet concentration and function, and white blood cell count were measured at baseline and variable time points after ischemia. Renal histopathology was evaluated on days 3, 6, 12, 21, 42, and 70 postischemia; changes in smooth muscle actin and interstitial collagen were examined. Following ischemia, whole animal glomerular filtration rate was significantly reduced (57% of baseline on day 6; P < .05). At the early time points, the ischemic kidneys exhibited severe acute epithelial necrosis accompanied by evidence of regeneration of tubules predominantly within the corticomedullary junction. At later periods, postischemic kidneys had evidence of tubular atrophy and interstitial inflammation with significantly more smooth muscle actin and interstitial collagen staining and interstitial fibrosis when compared with the contralateral control kidneys. This study characterizes the course of ischemic acute kidney injury in cats and demonstrates that ischemic acute kidney injury triggers chronic fibrosis, interstitial inflammation, and tubular atrophy in feline kidneys. These late changes are typical of those observed in cats with naturally occurring chronic kidney disease.

Chronic Kidney Disease in Aged Cats: Clinical Features, Morphology, and Proposed Pathogeneses.

Chronic kidney disease (CKD) is the most common metabolic disease of domesticated cats, with most affected cats being geriatric (>12 years of age). The prevalence of CKD in cats exceeds that observed in dogs, and the frequency of the diagnosis of CKD in cats has increased in recent decades. Typical histologic features include interstitial inflammation, tubular atrophy, and fibrosis with secondary glomerulosclerosis. In contrast to people and dogs, primary glomerulopathies with marked proteinuria are remarkably rare findings in cats. Although a variety of primary renal diseases have been implicated, the disease is idiopathic in most cats. Tubulointerstitial changes, including fibrosis, are present in the early stages of feline CKD and become more severe in advanced disease. A variety of factors-including aging, ischemia, comorbid conditions, phosphorus overload, and routine vaccinations-have been implicated as factors that could contribute to the initiation of this disease in affected cats. Factors that are related to progression of established CKD, which occurs in some but not all cats, include dietary phosphorus intake, magnitude of proteinuria, and anemia. Renal fibrosis, a common histologic feature of aged feline kidneys, interferes with the normal relationship between peritubular capillaries and renal tubules. Experimentally, renal ischemia results in morphologic changes similar to those observed in spontaneous CKD. Renal hypoxia, perhaps episodic, may play a role in the initiation and progression of this disease.