Metalloproteinases and their inhibitors are influenced by inhalative glucocorticoid therapy in combination with environmental dust reduction in equine recurrent airway obstruction

Abstract

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.

Clinical effect of corticosteroids in asthma‐affected horses: A quantitative synthesis

“…The results were not affected by the method of induction of clinical signs, type of inhaler device, environmental management or the professional level of the person administering the inhaled drugs. The few studies performed to assess the effect of corticosteroids using a clinical score recruited exclusively RAO-affected horses [28][29][30][31][32][33]. Consequently, the current meta-analysis cannot provide specific evidence on the clinical role of corticosteroids in IAD-affected horses.…”

“…***P<0.001 vs. control. Score references: Barton score , Rush score , Tesarowski score , Robinson score . IM , intramuscular; Inh., inhalation; IV , intravenous; OS : per os; SA , single administration.…”

“…Data obtained from 80 equine asthma‐affected horses were extracted from 6 studies that investigated the clinical effect of one or more corticosteroids. Three studies used corticosteroids administered via both inhalation and systemic route , two studies used exclusively the systemic forms of corticosteroids , and one study used only inhaled corticosteroids . All studies were published between 2003 and 2016, and the average duration of the clinical trials was 12 days.…”

Equine Asthma: Current Understanding and Future Directions

“…In horses with severe EA, MMPs, TIMPs, and their ratios are useful in the evaluation of the severity of respiratory disease and in identifying subclinical cases (91). Furthermore, MMP-2, MMP-9, TIMP-1, and TIMP-2 are significantly decreased after therapy with inhaled glucocorticoid therapy (171).…”

Role of neutrophils in equine asthma

“…Several alternative treatments with proposed resolution effects on inflammation have been evaluated. These include the optimization of GC treatment protocols (Cesarini et al , 2006; DeLuca et al , 2008; Robinson et al , 2009; Leclere et al , 2010; Franke and Abraham, 2014; Barton et al , 2016), autologous bone marrow-derived mononuclear cell therapy (Barussi et al , 2016), nanoparticulate immunotherapy (Klier et al , 2015), and tamoxifen treatment (Sarmiento et al , 2013; Perez et al , 2016; Borlone et al , 2017). Tamoxifen promotes early neutrophil apoptosis and dampens the chemotactic index and respiratory burst production in vitro (Borlone et al , 2017).…”