Prolonged Treatment with Inhaled Corticosteroids does not Normalize High Activity of Matrix Metalloproteinase-9 in Exhaled Breath Condensates of Children with Asthma

Abstract

The airway remodeling in asthma is associated with increased amount of matrix metalloproteinase (MMP)-9. High levels of MMP-9 were found in mucosal biopsies, sputum and in exhaled breath condensates (EBC) of asthma patients. However, there are no data concerning real in vivo activity. Inhaled corticosteroids are effective in asthma control, but it is unclear, whether they only attenuate inflammation, or also protect against progressive remodeling of respiratory tract. Therefore, the aim of the study was to assess the amount and activity of MMP-9 in context of pro-inflammatory cytokines (IL-6, IL-8 and tumor necrosis factor, TNF), measured in EBC of asthma-suffering children, treated with inhaled steroids. The study involved 27 children with asthma, continuously treated with inhaled fluticasone propionate, and 22 healthy controls. In addition to routine clinical screening, the selected cytokines in EBC were analyzed using Ultrasensitive ELISA, whereas activity of MMP-9 was assessed using a novel immunozymography method. Despite chronic treatment with inhaled steroids mean MMP-9/EBC activity in asthma group was significantly higher than in healthy controls. Moreover, high MMP-9/EBC in asthma-suffering children significantly correlated with IgE serum levels. The IL-6 and IL-8 concentration was below the detection limit in all EBC samples. TNF/EBC levels were similar in both, asthma and healthy children. We hypothesize that MMP-9 hyperactivity in asthma may be closely related to high IgE serum levels. Our results suggest that inhaled steroids may be ineffective to prevent asthma-associated airway remodeling. Finally, we emphasize the necessity of further research focused on MMP-9 inhibition in asthma treatment.

Matrix Metalloproteinases in Asthma-Associated Airway Remodeling – Dr. Jekyll or Mr. Hyde ?

“…[109] Unexpectedly, data from clinical studies in asthmatic patients are limited and disappointing. [27,110] In particular, no significant decrease in levels and/or activity of MMP-9 was observed after prolonged therapy with ICS in patients with asthma. [27,111] This finding may suggest that inhaled corticosteroids alone could not be as effective in preventing asthma-associated airway remodeling, as postulated previously.…”

“…The samples were obtained using various methods of collection and/or various material, among them serum or plasma, mucosal biopsies, induced sputum, broncho-alveolar lavage (BAL) fluid and, most recently, exhaled breath condensates (EBC). [27][28][29][30][31] Majority of studies concerned MMP-9, however, other MMPs, including MMP-1, -2, -3, or -12 were also studied. It is noteworthy that substrate specificity of mentioned MMPs entirely enables their self-sufficient work with full repertoire of ECM components.…”

“…Nevertheless, there is strong evidence that functional and structural changes in bronchial wall are also contributed by other producers of MMPs -epithelial cells, bronchial smooth myocytes, fibroblasts and mast cells. [5,27] In fact, recent studies have shown that epithelium-and myocytes-derived metalloproteinases may be involved in pathogenesis of asthma and asthma-associated remodeling much earlier, even before clinical manifestation of first symptoms. That hypothesis emerged as an ancillary result of embryological studies, focused on development of bronchial tree.…”

Where does current and future pediatric asthma treatment stand? Remodeling and inflammation: Bird's eye view

“…Another study that evaluated the change in MMP‐9 Levels in exhaled breath condensate from children with asthma demonstrated that this protease is significantly increased in asthma and steroid treatment fails to decrease the levels significantly. MMP‐9 is one of the enzymes that plays role in tissue turnover and wound healing and is proposed to play an important role in airway remodeling . These findings question the clinical utility of the lab findings that support steroid effect on remodeling, reported above.…”

“…Many different cytokines such as IL‐4 and IL‐13, growth factors like transforming growth factor beta and epidermal growth factor as well as cellular enzymes such as matrix metalloproteinases, plasminogen activator inhibitor‐1 are thought to contribute to airway remodeling in asthma . Either a protective mechanism or not, it is an outcome that decreases responsiveness to treatment; decreases reversibility of airflow obstruction and that is actually irreversible .…”