In chronic respiratory disease, matrix metalloproteinases (MMPs) contribute to pathological tissue destruction when expressed in excess, while tissue inhibitors of metalloproteinases (TIMPs) counteract MMPs with overexpression leading to fibrosis formation. They may be out of balance in equine pneumopathies and serve as biomarkers of pulmonary inflammation. We hypothesized that MMPs and TIMPs correlate to clinical findings and bronchoalveolar lavage fluid cytology in different equine chronic pneumopathies. Using a scoring system, 61 horses were classified controls as free of respiratory disease (n = 15), recurrent airway obstruction (RAO, n = 17), inflammatory airway disease (IAD, n = 18), or chronic interstitial pneumopathy (CIP, n = 11). Zymography and equine MMP and TIMP assays were used to detect MMP-2, MMP-8, MMP-9 as well as TIMP-1, and TIMP-2 in BALF supernatant. MMP-2, TIMP-1, and TIMP-2 concentrations were significantly increased in RAO and IAD compared to controls. MMP-9 concentration and MMP-8 activity evaluated by fluorimetry were significantly increased in RAO, IAD, and CIP. These results were confirmed by zymography for MMP-2 and MMP-9 activity in 52 horses. In conclusion, MMPs and TIMPs correlate well with clinical and cytologic findings. These findings support the usefulness of MMPs, TIMPs, and their ratios to evaluate the severity of respiratory disease and may help to identify subclinical cases.
BackgroundOverexpression of matrix-metalloproteinases (MMPs) has been shown to lead to tissue damage in equine recurrent airway obstruction (RAO), as a misbalance with their natural inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), occurs. This favors irreversible pulmonary fibrosis formation. Increased levels of MMPs, TIMPs or altered ratios between them can be used as biomarkers of respiratory disease. We hypothesized that levels of MMPs, TIMPs and their ratios correlate with improvement in clinical findings and bronchoalveolar lavage fluid (BALF) cytology after 10 days of inhalative glucocorticoid therapy and environmental dust reduction (EDR) and may be used to monitor treatment success.Ten horses with a history of RAO participated in a prospective clinical study. Clinical and cytological scoring was performed before and after inhalative therapy using budesonide (1500 μg BID over 10 days) and EDR (bedding of wood shavings and wet hay as roughage). Gelatin zymography was performed for qualitative and semi-quantitative evaluation of MMP-2 and MMP-9 in BALF supernatant, while fluorimetry was used to evaluate MMP-8 activity. Additionally, specific equine ELISA assays were used for quantitative assessment of MMP-2, MMP-9, TIMP-1 and TIMP-2.ResultsA significant reduction in the total and several single parameters of the clinical score were found after 10 days of inhalative therapy and EDR. The concentrations of MMP-2, MMP-9, TIMP-1 and TIMP-2 (ELISA) as well as their activities (MMP-2 and MMP-9 zymography and MMP-8 fluorimetry) were significantly decreased after therapy. Significant improvements in MMP-8/TIMP-1 and MMP-8/TIMP-2 ratios were also found, differences between other ratios before and after therapy were insignificant.ConclusionsMetalloproteinases and their inhibitors, in particular MMP-9 and TIMP-2, are valuable markers for clinical improvement in RAO.
Objectives. Inhalation of immunostimulatory bacterial DNA segments (cytosine-phosphate-guanosine-oligodeoxynucleotides, CpG-ODN) normalizes clinical and cytologic parameters in severe equine asthma. We hypothesized that CpG-ODN inhalation also reduces the misbalance of elastinolytic activity in asthmatic horses. Methods. Twenty asthmatic horses diagnosed by clinical examinations using a scoring system were included. All horses inhaled CpG-ODNs for 14 days in 2-day intervals. Matrix metalloproteinase (MMP-2/-9) and tissue inhibitors of metalloproteinase (TIMP-1/-2) concentrations were measured in tracheal aspirates using equine sandwich ELISAs before and 2 and 6 weeks after CpG-ODN inhalation. Results. MMP and TIMP concentrations correlated with the results of clinical scoring in all stages of equine asthma. Inhalation therapy led to significant reductions in clinical scores. MMP-2, MMP-9, and TIMP-2 concentrations were significantly reduced immediately, and all MMP and TIMP concentrations 6 weeks after therapy. Discussion. In equine asthma, overexpression of MMPs contributes to pathological tissue destruction, while TIMPs counteract MMPs with overexpression leading to fibrosis formation. The results of this study show that CpG-ODN inhalation may be an effective therapy to address a misbalance in equine asthma. Conclusions. Misbalance of elastinolytic activity seems to improve by CpG-ODN inhalation for at least 6 weeks posttherapy, which may reduce the remodeling of the extracellular matrix. Further studies should evaluate this effect in comparison to glucocorticoid inhalation therapy. Significance. CpG-ODN inhalation may be an effective therapy in the prevention of pulmonary fibrosis formation in equine asthma.
Cardiac biomarkers are important tools for monitoring disease progress and can monitor progression of therapy. Endothelin-1 (ET-1) has been studied for its use as a cardiac biomarker in human and small animal medicine while in horses with cardiac disease it has not been evaluated yet. The objective of the present study was to determine the concentration of plasma ET-1 in healthy horses and compare it with ET-1 concentration in horses with cardiac disease during rest and after exercise. Fifty four horses admitted to the Equine Clinic of Free University of Berlin were used in the present study, of which 15 horses were clinically healthy with no evidence of cardiac disease (Group 1), 22 horses suffered from cardiac disease with normal heart dimensions (Group 2) and 17 horses with cardiac disease and enlarged heart diameters (Group 3). Clinical examination, electrocardiography and echocardiography were performed. Endothelin-1 concentration was determined using ET-1 ELISA kit. The concentration of plasma ET-1 was significantly increased in horses with cardiac disease and normal cardiac dimensions (Group 2) and in horses with cardiac disease and enlargement of the left atrium (Group 3) compared to its concentration in clinically healthy horses (Group 1). In addition, the concentration of plasma ET-1 after exercise was significantly increased in diseased horses compared to its concentration at rest. Detection of ET-1 plasma concentration in horses at rest may be useful for detecting horses with changes in left atrial cardiac dimensions.
A total of 32 horses examined from the period between July 2015 and July 2017 were included in the present study. Horses were grouped according to the results of the general clinical examination and the diagnosis. Ten horses were apparently healthy used as control horses (Group I) and 22 research Article Abstract | The aim of this study was to measure the concentration of the plasma D-dimer in healthy horses and in horses with colic and to compare it before and after therapy. Thirty-two horses were included; 22 horses showed signs of abdominal pain. Horses were grouped according to clinical and laboratory examination results into healthy horses (Group I, n=10); horses with colic associated with enteritis and/or colitis (Group II, n=16) were presented with moderate intermittent abdominal pain with increased peristalsis and increased frequency of defecation; horses with colic associated with impaction of the intestine (Group III, n=6) were presented with severe abdominal pain and decreased fecal output. There was significant increase in the concentration of plasma D-dimer in horses with impaction of the intestine and horses with enteritis and/or colitis compared to clinically healthy horses. Therapeutic trials resulted in improvement of the D-dimer concentration where the concentration of plasma D-dimer was significantly decreased in horses with enteritis and/or colitis and in horses with impaction of the intestine after therapy compared to its concentration before therapy. In conclusion, D-dimer is a sensitive marker for detection of excessive fibrinolysis in horses. Higher concentration of plasma D-dimer is observed in severe cases of colic and might reflect poor prognosis.
Summary: Over the last years local and systemic inflammatory markers of chronic pneumopathies have gained increasing interest in research, as the pathogenesis of Recurrent airway obstruction (RAO) and Inflammatory airway disease (IAD) remains not fully elucidated in several details. In human medicine, Asthma bronchiale and Chronic obstructive pulmonary disease (COPD) have been found to be influenced by systemic inflammatory processes and the other way around. Inflammation, coagulation and fibrinolysis as well as extracellular remodeling show close interactions. Cytology of bronchoalveolar lavage fluid and tracheal wash is commonly used to evaluate the severity of local inflammation in the lung. Interleukins involved in the chemotaxis of neutrophils like Interleukin 8, 17 and 23 have been studied. Chronic obstructive pneumopathies lead to remodeling of bronchial walls and lung parenchyma, ultimately causing fibrosis. Matrix-metalloproteinases (MMPs) are discussed as the most important proteolytic enzymes during remodeling in human medicine. In the horse, MMP 9 seems to be a central player in chronic respiratory disease as well. A systemic involvement has been shown for RAO by increased acute-phaseproteins like serumamyloid A and haptoglobin in peripheral blood during exacerbation. Studies focusing on these and further possible inflammatory markers for chronic respiratory disease in the horse are discussed in this review of literature.Keywords: Inflammatory markers / horse / respiratory disease / recurrent airway obstruction / RAO / Diagnostischer Wert verschiedener Entzündungsmarker bei chronischen Atemwegserkrankungen des Pferdes -eine ÜbersichtIn den letzten Jahren häufen sich Untersuchungen zu verschiedenen lokalen und systemischen Entzündungsmarkern bei chronischen Pneumopathien des Pferdes, da das Verständnis der Pathogenese von Recurrent airway obstruction (RAO) und Inflammatory airway disease (IAD) weiterhin nicht vollständig geklärt ist. Ein Blick in die Humanmedizin zeigt, dass das Asthma bronchiale und die Chronic obstructive pulmonary disease (COPD) durchaus in Zusammenhang stehen mit systemischen inflammatorischen Prozessen, so dass sich die lokalen Prozesse in der Lunge und systemische Entzündungsreaktionen gegenseitig beinflussen. Entzündung, Koagulation und Fibrinolyse sowie das extrazelluläre Remodelling sind eng miteinander verknüft. Zytologische Untersuchungen der bronchoalveolären Lavageflüssigkeit und des Tracheobronchialsekrets stellen die gebräuchlichste Methode dar, den Schweregrad der lokalen Entzündung zu beurteilen. Hierbei ergeben sich Zusammenhänge zu Interleukinen, die an der Chemotaxis neutrophiler Granulozyten beteiligt sind, wie beispielsweise Interleukin 8, 17 und 23. Chronisch obstruktive Pneumopathien führen langfristig zu chronischen Umbauprozessen der Bronchienwände und des Lungenparenchyms (Remodelling), die mit der Bildung von Fibrosen einhergehen. Matrix-Metalloproteinasen (MMPs) gelten in der Humanmedizin als wichtigste proteolytische Enzyme bei diesem Remodelling und auch...
This study aimed to compare the hemato-biochemical parameters in cats suffered from FLUTD with those of healthy cats, and to evaluate the inflammatory process by measuring serum amyloid A, alpha-1-Acid glycoprotein, and plasma fibrinogen concentrations. Cats frequently suffer from feline lower urinary tract disease (FLUTD), which causes acute renal failure, electrolyte buildup, and acid-base imbalance. Acute-phase proteins can be used to monitor the inflammatory processes of feline lower urinary tract disease.The present study included thirty cats of both sexes, nine cats defined as clinically healthy cats and 21 cats with signs of idiopathic cystitis and/ or urethral obstruction for up to 24 hours were defined as cat with FLUTD group. Blood samples were collected from cephalic vein for hematological, biochemical assays and the measurement of acute-phase protein concentrations, including SAA, AGP, and fibrinogen. Serum SAA and AGP were measured using commercial ELISA kits.In cats with FLUTD, the total white blood cell count, neutrophils, and platelets count increased significantly, as did the mean values of hematological and biochemical indices. However, there was a significant decrease in the mean value of red blood cells, hemoglobin, and PCV. Blood urea nitrogen, creatinine, total proteins, albumin, potassium, and phosphorus levels all increased significantly, while sodium and chloride levels decreased significantly. When compared to clinically healthy cats, plasma fibrinogen, serum alpha-1- acid glycoprotein, and serum amyloid A levels were significantly higher in cats with FLUTD. There was a significant positive correlation between the concentrations of acute phase proteins biomarkers (SAA, AGP, and fibrinogen) and blood urea nitrogen and creatinine. It is concluded that, in cats with FLUTD, serum amyloid A, AGP, and fibrinogen could be employed as an indicator of inflammatory processes.
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