Effect of eosinophil peroxidase on airway epithelial permeability in the guinea pig

Abstract

Increased numbers of eosinophils and increased concentrations of plasma proteins have been found in the airways of patients with mild asthma. We used an intact guinea pig trachea model to investigate the role of eosinophil peroxidase (EPO) in altering the function of the airway epithelial barrier, EPO in the presence of hydrogen peroxide (H2O2) and bromide (Br−) catalyzes the production of hypobromous acid (HOBr), which is felt to have a toxic effect on airway epithelial cells. An intact guinea pig trachea was mounted on an apparatus in a way that would allow the tracheal epithelium to be exposed to different solutions. Following these exposures, a test solution containing 14C‐sucrose (S), 3H‐inulin (I), and FITC‐dextran‐20 (D) was placed in the tracheal lumen and positioned in the center of the segment for 90 minutes. Flux of these molecules across the epithelial barrier into a bath was measured, and the permeability (P) was calculated for each molecule to quantify epithelial barrier function. Light and electron micrographic studies were performed to assess cellular damage. We found that there was a dose response to EPO (in the presence of fixed amounts of H2O2 and Br−). EPO at 7.3 × 10−7 M caused no increase in P over controls (Ringer's solution alone) for S, I, or D (P > 0.05), whereas EPO at 2.7 × 10−6 M caused a significant increase in P over controls (P = 0.008) for all test molecules. Light and electron micrographs of the latter tracheas showed no evidence of microscopic changes despite the increased P. Further testing verified that the increase in permeability was caused by the EPO catalyzed reaction and not the individual substrates themselves, and that the reaction was inhibited by a peroxidase inhibitor. We conclude that EPO can alter the barrier function of the airway epithelium before gross cellular damage becomes visible. We hypothesize that changes in the tight junctions are responsible for the alteration in the barrier function of the airway epithelium and that this may play an important role in the pathophysiology of mild asthma. Pediatr Pulmonol. 1996; 21:159–166. © 1996 Wiley‐Liss, Inc.

Analysis of Trace and Major Elements in Bronchoalveolar Lavage Fluid of Mycoplasma Bronchopneumonia in Calves

“…A structurally and functionally distinct enzyme from neutrophil myeloperoxidase has the unique ability to use halides or pseudohalides (X − ) and H 2 O 2 derived from the respiratory burst to generate cytotoxic hypohalous acids, especially hypobromous acid (HOBr) [23,24]. The eosinophil peroxidase (EPO), such as EPO-H 2 O 2 -Br − system, is also an effective cytotoxin for multiple targets such as multicellular worms or parasites, bacteria, viruses, and host cells [23].…”

“…The eosinophil peroxidase (EPO), such as EPO-H 2 O 2 -Br − system, is also an effective cytotoxin for multiple targets such as multicellular worms or parasites, bacteria, viruses, and host cells [23]. Both HOBr and the EPO-H 2 O 2 -Br − system are involved in many of the pathophysiological features of inflamed respiratory disease [24].…”

Eosinophils Are a Major Source of Nitric Oxide-Derived Oxidants in Severe Asthma: Characterization of Pathways Available to Eosinophils for Generating Reactive Nitrogen Species

“…Thus it is reasonable to speculate that oxidative modification of critical biological targets in asthmatic airways may contribute to the pathophysiological sequelae of the disease. Particularly given the known toxicity of HOBr and the EPO-H 2 O 2 -Br Ϫ system to eukaryotic cells in culture (73,74), and their capacity to elicit many of the pathophysiologic features of asthma, such as epithelial cell damage and sloughing, airway hyperreactivity, bronchoconstriction, ␤-adrenergic dysfunction, mucus hyper secretion, microvascular leak, and edema (75)(76)(77)(78)(79)(80).…”

In vivo neutralization of eosinophil-derived major basic protein inhibits antigen-induced bronchial hyperreactivity in sensitized guinea pigs.

“…Cationic proteins also promote airway vascular leakage (24,28), which, in turn, may alter epithelial permeability and facilitate the access of inhaled agonist to the smooth muscle, leading to an amplification of the bronchial responses. However, the inhibition of bronchial hyperreactivity by rabbit antiguinea pig MBP Igs we reported here is unlikely to result from a blockade of vascular leakage, since changes in acetylcholineinduced bronchoconstriction were observed at a late time point (72 h) after antigen challenge, when increase in vascular permeability has already resolved.…”