Aerosolized human neutrophil elastase induces airway constriction and hyperresponsiveness with protection by intravenous pretreatment with half-length secretory leukoprotease inhibitor.

Abstract

This study was designed to determine the effects of inhaled human neutrophil elastase (HNE) on airway constriction and airway responsiveness, and to examine the protection by an intravenous recombinant half-length secretory leukoprotease inhibitor, r1/2SLPI in guinea pigs. Aerosol inhalation of HNE (250 microgram/ml, for 3 min) caused a transient but significant airway constriction, in which lung resistance (RL) increased from 194 +/- 18 (mean +/- SEM) to 461 +/- 42 cm H2O/L/s (p < 0.001). Thirty minutes after the end of HNE inhalation, airway responsiveness to intravenous 5-hydroxytryptamine (5-HT) was significantly increased. The provocative dose causing a 200% increase in RL (PD200) was significantly decreased from 10.0 +/- 1.2 to 6.5 +/- 0.8 microgram/kg (p < 0.001). Forty-five minutes after the end of HNE inhalation, total cells in bronchoalveolar lavage fluid (BALF) were significantly increased (p < 0.05). Histologic study of intrapulmonary bronchi demonstrated an acute inflammatory response characterized by damage to the epithelium, airway obstruction by mucus plugs, and recruitment of mononuclear and polymorphonuclear cells to the bronchial epithelium. r1/2SLPI (30 mg/kg) injected 5 min before the initiation of HNE inhalation significantly inhibited the airway constriction (p < 0.05), the airway hyperresponsiveness (p < 0.01), and the increase of cells in BALF (p < 0.05). The present data suggest that HNE plays a role in the induction of airway constriction and airway hyperresponsiveness in various inflammatory lung diseases with pulmonary neutrophil infiltration, such as chronic obstructive pulmonary diseases (COPD) and possibly bronchial asthma. r1/2SLPI may be useful as an antiprotease treatment.

Neutrophilic airway inflammation and IL‐17

“…In addition, this specific indicator of neutrophil activity can cause bronchial hyperresponsiveness and tissue remodelling in A. LindØn 1 , M. Adachi rodent airways in vivo and in collagen gels in vitro (34)(35)(36)(37)(38), thus providing additional evidence for functional impact of neutrophils in the airways and lungs. In fact, neutrophil elastase can be detected in several diseases of the airways and lungs.…”

The role of T helper 17 (Th17) and regulatory T cells (Treg) in human organ transplantation and autoimmune disease

“…This latter mechanism may be critically important as neutrophilic infiltrates and neutrophil enzymatic activity correlate with the degree of bronchial hyperreactivity in patients with asthma [81]. IL-17-induced IL-6 release may have dual pathological significance, as IL-6 promotes neutrophil elastase release [82] (elastase activity is thought to be a key mediator in the pathogenesis of chronic airway diseases [83,84] and reciprocally controls activity of neutrophil IL-6 [85]) and is one of the mechanisms by which IL-17 stimulates release of mucin by respiratory epithelial cells [86]. Furthermore, IL-6 is important in the generation of IL-17-producing cells (mouse data, see below).…”

Neutrophils, interleukin-17A and lung disease

“…There is substantial evidence suggesting that neutrophil elastase degrades elastin, a key structural lung component that prevents small airways from collapsing, and that this leads to an emphysema-like condition in the lungs, and possibly also to remodelling of airway tissue [64][65][66][67][68]. Human neutrophil elastase also augments the fibroblast-mediated contraction of collagen gels in vitro, an observation underlining the potential remodelling capacity of this serine proteinase [68,69].…”

“…Interestingly, neutrophil elastase appears to substantially contribute to secretion in airway gland cells from humans and other mammals in vitro, as well as in the upper airways of dogs in vivo [70][71][72]. Neutrophil elastase can also cause nonspecific bronchial hyperresponsiveness in guinea pig airways in vivo [64,65]. There is even data from in vitro studies demonstrating that peptide fragments from human elastin that has been degraded using human neutrophil elastase cause chemotaxis of human blood monocytes and calf skin fibroblasts; evidence compatible with this elastase causing the recruitment of cells other than neutrophils and thus perpetuating inflammation at sites of neutrophil accumulation [73,74].…”