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.
Bronchial asthma is a disease characterized by chronic airway inflammation associated with the accumulation and activation of inflammatory cells, such as eosinophils, in the bronchial wall and airway lumen. Eosinophils at the site of inflammation release preformed and newly synthesized mediators, including eosinophil cationic protein, major basic protein, leukotriene C 4 , and reactive oxygen. These mediators contribute to the formation of the pathological features of asthmatic airways such as bronchoconstriction, mucus hypersecretion, microvascular leakage, submucosal edema, and epithelial shedding, which lead to the clinical features of asthma, hyperresponsiveness, and airway narrowing. [1][2][3][4][5] Eosinophils cultured in the absence of hematopoietic cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-5 undergo apoptosis, which is physiologic cell death characterized by morphologic changes such as membrane blebbing and nuclear condensation, and by the degradation of DNA into oligonucleosomesized fragments showing a "ladder" pattern on agarose gel. [6][7][8] Apoptotic eosinophils have been shown to be removed from the tissue without releasing inflammatory mediators after ingestion by macrophages, 8) which is believed to be one of the important mechanisms in the resolution of inflammation.9) GM-CSF and IL-5, which have been detected in sputum, bronchoalveolar lavage fluid, and bronchial tissues from asthmatics, 5) prolong the survival of tissue eosinophils through the prevention of apoptosis, 10,11) leading to the development and maintenance of airway inflammation. Therefore the induction of apoptosis in eosinophils would be beneficial in the treatment of asthma. The induction of apoptosis in airway eosinophils by the administration of anti-Fas antibody or inhaled steroid is reported to be associated with the reduction or termination of asthmatic airway inflammation in vivo. 12,13) cAMP is well known as a second messenger mediating intracellular signal transduction evoked by the binding of agonists to their cell-surface receptors. The concentration of intracellular cAMP is dependent on the catalysis rate of ATP to cAMP by adenylate cyclase and of cAMP to 5Ј-adenosine monophosphate by cyclic nucleotide phosphodiesterases (PDEs).14) PDEs comprise at lease 11 families containing, in total, more than 50 different PDE enzyme variants, the differentiation of which is based on the primary protein and cDNA sequences, substrate specificity, regulation of enzymatic activity, and calcium/calmodulin dependence.15) The increased concentration of intracellular cAMP is known to suppress the functions of inflammatory cells.14,16) With regard to eosinophils of which the PDE isoenzyme is exclusively type 4, 17) selective inhibitors of PDE 4 and theophylline, a nonselective PDE inhibitor, have been shown to inhibit chemotaxis, adhesion, degranulation, and the release of active oxygen by an increase in the cAMP content.14,16,18) Furthermore, PDE 4 inhibitors and theophylline, as well...
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