Extraesophageal reflux and reflux aspiration in dogs with respiratory diseases and in healthy dogs.

BACKGROUND: Salivary bile acids are used to diagnose extraesophageal reflux (EER) and to evaluate the risk of reflux aspiration that is associated with respiratory diseases in dogs. OBJECTIVES: To study total bile acid (TBA) concentrations in saliva and in bronchoalveolar lavage fluid (BALF) to investigate EER and reflux aspiration in dogs with respiratory diseases and in healthy dogs. ANIMALS:  Thirty-one West Highland White Terriers (WHWTs) with idiopathic pulmonary fibrosis (IPF), 12 dogs with inflammatory airway disease (IAD), 6 dogs with recurrent pneumonia (RP), 26 brachycephalic dogs (BD), 27 healthy WHWTs (HW), 52 healthy dogs (HD). All privately-owned dogs. METHODS: Saliva and BALF were collected from dogs in each group. RESULTS: Salivary TBA concentrations were higher in IPF (median 0.1692 µM, interquartile range [IQR] 0.1115-0.2925 µM, Cohen's d 3.4, 95% confidence interval [CI] 2.2-4.0, P < .001) and BD (0.0256 µM, IQR 0.0086-0.0417 µM, d 0.5, CI -0.1 to 1.1, P = .003) compared to HD (0 µM, IQR not quantifiable [n.q.]-0.0131 µM). Bronchoalveolar lavage fluid TBA concentrations were higher in IPF (0.0117 µM, IQR 0.0048-0.0361 µM, d 0.5, CI 0-1.1, P < .001) compared to HD (0 µM, IQR n.q.-0.0074 µM). CONCLUSION AND CLINICAL IMPORTANCE: Extraesophageal reflux and reflux aspiration occur in healthy dogs and those with respiratory diseases.

Polycythemia in dogs with chronic hypoxic pulmonary disease.

BACKGROUND: Prolonged tissue hypoxia caused by chronic pulmonary disease is commonly regarded as an important mechanism in the development of secondary polycythemia, but little clinical data are available to support this hypothesis. OBJECTIVE: To study the prevalence and severity of erythrocytosis accompanying chronic hypoxic pulmonary disease in dogs. ANIMALS: Forty-seven dogs with hypoxic chronic pulmonary disease, 27 dogs with nonhypoxic chronic pulmonary disease, and 60 healthy controls. METHODS: Dogs with chronic pulmonary disease and chronic hypoxemia (partial pressure of arterial oxygen [PaO2 ] < 80 mm Hg on at least 2 arterial blood gas measurements a minimum of 1 month apart) were identified retrospectively from patient records. Association between arterial oxygen and red blood cell parameters was analyzed using Pearson's correlation coefficients and multivariable linear regression analysis. RESULTS: Red blood cell parameters measured at the end of the hypoxemia period were within the laboratory reference range in most dogs. In chronically hypoxemic dogs, hematocrit (Hct) was increased in 4/47 (8.5%; 95% confidence interval [CI], 0-17) dogs, erythrocyte count (Erytr) was increased in 12/47 (26%; 95%CI, 13-38) dogs and hemoglobin concentration (Hb) was increased in 3/47 (6.4%; 95%CI, 0-14) dogs. No marked polycythemia (Hct ≥65%) was noted in any of the dogs. Red blood cell parameters were not associated with the severity of hypoxemia (correlation to PaO2 : Erytr, r = -.14; Hb, r = -.21; Hct, r = -.14; P > .05 for all). CONCLUSIONS AND CLINICAL IMPORTANCE: Polycythemia is uncommon, and usually mild if present, in dogs with chronic hypoxia caused by pulmonary disease.

Quantitative proteomic analysis of bronchoalveolar lavage fluid in West Highland white terriers with canine idiopathic pulmonary fibrosis.

BACKGROUND: Canine idiopathic pulmonary fibrosis (CIPF) is a chronic, progressive, interstitial fibrosing lung disease, manifesting as cough, exercise intolerance and ultimately, dyspnea and respiratory failure. It mainly affects West Highland white terriers (WHWTs), lacks curable treatment and has a poor prognosis. Aspiration of gastroesophageal refluxate may play a role in the development of CIPF. In the first part of this study, we completed label-free quantitative proteomic analysis of bronchoalveolar lavage fluid (BALF) from CIPF and healthy WHWTs. In the second part, we evaluated potential protein markers of reflux aspiration from canine gastric juice and vomitus and whether these were present in BALF from the two groups. RESULTS: Across all BALF samples, 417 proteins were identified, and of these, 265 proteins were identified by two or more unique tryptic peptides. Using the 265 high confidence assignments, the quantitative proteome profiles were very similar in the two cohorts, but they could be readily resolved by principal component analysis on the basis of differential protein expression. Of the proteins that were differentially abundant in the two groups, several (including inflammatory and fibrotic markers) were elevated in CIPF, and a smaller, more diverse group of proteins were diminished in CIPF. No protein markers indicative of reflux aspiration were identified. CONCLUSIONS: Label-free proteomics allowed discrimination between CIPF and healthy WHWTs, consistent with fibrotic process but did not provide clear evidence for gastrointestinal aspiration. The measurement of proteins may provide a proteomics signature of CIPF that could be used to evaluate treatment options.

Matrix metalloproteinase-2, -7, and -9 activities in dogs with idiopathic pulmonary fibrosis compared to healthy dogs and dogs with other respiratory diseases.

BACKGROUND: Canine idiopathic pulmonary fibrosis (CIPF) is a chronic, interstitial lung disease that mainly affects West Highland white terriers (WHWTs) and is characterized by excessive deposition of extracellular matrix (ECM) in the lung. Matrix metalloproteinases (MMPs) participate in remodeling of ECM. OBJECTIVES: To compare metalloproteinase-2, -7 and -9 activities in blood or bronchoalveolar lavage fluid (BALF) samples or both of CIPF WHWTs with healthy WHWTs, healthy dogs of other breeds, and dogs with other lung diseases and determine if these MMPs could be used as diagnostic and prognostic markers for CIPF. ANIMALS: Forty-four CIPF WHWTs, 24 dogs with chronic bronchitis (CB), 17 with eosinophilic bronchopneumopathy (EBP), 10 with bacterial pneumonia, 39 healthy WHWTs, and 35 healthy dogs of other breeds. METHODS: Cross-sectional observational study. Pro-MMP and active MMP activities were analyzed by zymography. RESULTS: In serum, significantly higher (P < .01) pro-MMP-7 activities were observed in CIPF WHWTs compared to healthy dogs of other breeds, dogs with CB and dogs with EBP. In BALF of CIPF WHWTs, both pro-MMP-9 and pro-MMP-2 activities were significantly higher (P < .01) compared to healthy WHWTs, but these differences were not detected in plasma. The CIPF WHWTs had significantly higher (P < .05) activities of pro-MMP-9 compared to dogs with CB and of pro-MMP-2 compared to dogs with CB and EBP. No statistically significant prognostic factors were observed in CIPF WHWTs. CONCLUSIONS AND CLINICAL RELEVANCE: Serum MMP-7 and BALF MMP-2 and -9 potentially may be useful diagnostic markers but not prognostic markers for CIPF.

Update on Canine Idiopathic Pulmonary Fibrosis in West Highland White Terriers.

Canine idiopathic pulmonary fibrosis (CIPF) is a chronic, progressive, interstitial lung disease (ILD) affecting older West Highland white terriers (WHWTs). According to one classification, CIPF is a familial fibrotic ILD in the group of idiopathic interstitial pneumonias. Etiology is unknown but likely arises from interplay between genetic and environmental factors. CIPF shares features with human idiopathic pulmonary fibrosis and human nonspecific interstitial pneumonia. This article describes clinical signs, findings in physical examination, arterial oxygenation, diagnostic imaging, bronchoscopy, bronchoalveolar lavage, histopathology, disease course, and outcome of WHWTs with CIPF; compares canine and human diseases; summarizes biomarker research; and gives an overview of potential treatment.

Reflux aspiration in lungs of dogs with respiratory disease and in healthy West Highland White Terriers.

BACKGROUND: Gastroesophageal reflux and microaspiration (MA) of gastric juice are associated with various human respiratory diseases but not in dogs. OBJECTIVE: To detect the presence of bile acids in bronchoalveolar lavage fluid (BALF) of dogs with various respiratory diseases. ANIMALS: Twenty-seven West Highland White Terriers (WHWTs) with canine idiopathic pulmonary fibrosis (CIPF), 11 dogs with bacterial pneumonia (BP), 13 with chronic bronchitis (CB), 9 with eosinophilic bronchopneumopathy (EBP), 19 with laryngeal dysfunction (LD), 8 Irish Wolfhounds (IWHs) with previous BPs, 13 healthy WHWTs, all privately owned dogs, and 6 healthy research colony Beagles METHODS: Prospective cross-sectional observational study with convenience sampling of dogs. Bile acids were measured by mass spectrometry in BALF samples. Total bile acid (TBA) concentration was calculated as a sum of 17 different bile acids. RESULTS: Concentrations of TBA were above the limit of quantification in 78% of CIPF, 45% of BP, 62% of CB, 44% of EBP, 68% of LD, and 13% of IWH dogs. In healthy dogs, bile acids were detected less commonly in Beagles (0/6) than in healthy WHWTs (10/13). Concentrations of TBA were significantly higher in CIPF (median 0.013 µM, range not quantifiable [n.q.]-0.14 µM, P < .001), healthy WHWTs (0.0052 µM, n.q.-1.2 µM, P = .003), LD (0.010 µM, n.q.-2.3 µM, P = .015), and CB (0.0078 µM, n.q.-0.073 µM, P = .018) groups compared to Beagles (0 µM, n.q.). CONCLUSION AND CLINICAL IMPORTANCE: These results suggest that MA occurs in various respiratory diseases of dogs and also in healthy WHWTs.

Assessment of CCL2 and CXCL8 chemokines in serum, bronchoalveolar lavage fluid and lung tissue samples from dogs affected with canine idiopathic pulmonary fibrosis.

Canine idiopathic pulmonary fibrosis (CIPF) is a progressive disease of the lung parenchyma that is more prevalent in dogs of the West Highland white terrier (WHWT) breed. Since the chemokines (C-C motif) ligand 2 (CCL2) and (C-X-C motif) ligand 8 (CXCL8) have been implicated in pulmonary fibrosis in humans, the aim of the present study was to investigate whether these same chemokines are involved in the pathogenesis of CIPF. CCL2 and CXCL8 concentrations were measured by ELISA in serum and bronchoalveolar lavage fluid (BALF) from healthy dogs and WHWTs affected with CIPF. Expression of the genes encoding CCL2 and CXCL8 and their respective receptors, namely (C-C motif) receptor 2 (CCR2) and (C-X-C motif) receptor 2 (CXCR2), was compared in unaffected lung tissue and biopsies from dogs affected with CIPF by quantitative PCR and localisation of CCL2 and CXCL8 proteins were determined by immunohistochemistry. Significantly greater CCL2 and CXCL8 concentrations were found in the BALF from WHWTs affected with CIPF, compared with healthy dogs. Significantly greater serum concentrations of CCL2, but not CXCL8, were found in CIPF-affected dogs compared with healthy WHWTs. No differences in relative gene expression for CCL2, CXCL8, CCR2 or CXCR2 were observed when comparing lung biopsies from control dogs and those affected with CIPF. In affected lung tissues, immunolabelling for CCL2 and CXCL8 was observed in bronchial airway epithelial cells in dogs affected with CIPF. The study findings suggest that both CCL2 and CXCL8 are involved in the pathogenesis of CIPF. Further studies are required to determine whether these chemokines might have a clinical use as biomarkers of fibrosis or as targets for therapeutic intervention.

Idiopathic pulmonary fibrosis in West Highland white terriers.

Canine idiopathic pulmonary fibrosis (CIPF) is a chronic, progressive, interstitial lung disease affecting mainly middle-aged and old West Highland white terriers. Other dogs, especially terriers, have been diagnosed with the disease. The cause is largely unknown, but it is likely to arise from interplay between genetic and environmental factors. CIPF shares several features with human idiopathic pulmonary fibrosis. This article summarizes the current literature; describes the findings in physical examination, arterial blood gas analysis, bronchoscopy, bronchoalveolar lavage, diagnostic imaging, and histopathology; compares the canine and human diseases; gives an overview of potential treatments; and discusses biomarker research.