muramidase and Pulmonary-Disease--Chronic-Obstructive

The respiratory tract presents a large and potentially vulnerable surface to inhaled microbes. It is coated by a thin layer of secretions generated by airway epithelial cells, submucosal glands, resident and recruited phagocytes (neutrophils, eosinophils, monocytes, and macrophages) and alveolar epithelial cells, as well as substances that enter from blood plasma. More than 80 years ago, Alexander Fleming observed that respiratory secretions have microbicidal and microbistatic properties. He described the activity of lysozyme, one of the principal polypeptides of these secretions. Since then, a number of additional antimicrobial components have been identified, and there is increasing insight into their complex interactions. This review is an update of my previous summary of this area.

Topics: Antimicrobial Cationic Peptides; Humans; Muramidase; Pulmonary Disease, Chronic Obstructive; Respiratory Mucosa; Respiratory Tract Diseases

Mucolytic agents are often used in Japan to ease excessive mucus production in patients with chronic obstructive pulmonary disease (COPD) or bronchial asthma (BA); the treatment ameliorates dyspnea and improves quality of life (QOL).. Efficacy and safety of lysozyme hydrochloride (LYS), an oral mucolytic enzyme preparation, for patients with COPD or BA were investigated.. This study was a placebo-controlled, double-blind, randomized, cross-over design. Twenty-four patients with COPD and twenty-four patients with BA were enrolled. LYS or placebo was administered for 28 days in each treatment period, with a 28-day washout between the first and second treatment periods. The results of spirometry, impulse oscillometry system (IOS) examination, fractional exhaled nitric oxide (FeNO) measurement, as well as the changes in the subjective symptoms, were evaluated after the treatment period.. On spirometry, airway function (FEV1) improved in patients with COPD after administration of LYS (LYS vs placebo: 0.08 L vs 0.029 L, p = 0.030). Similar trends were also found in %FEV1 in COPD patients. On IOS examination, resistance of the respiratory system at 5 Hz levels was significantly improved only in patients with COPD (LYS vs placebo: -0.455 cm H2O/L/s vs 0.095 cmH2O/L/s, p = 0.012). Similar trends were found in terms of the resistance of the respiratory system at 20 Hz, and of the reactance area. In the COPD assessment test, subjective symptoms also significantly improved in patients with COPD during the LYS treatment period (improvement rates-LYS vs. placebo: 69.6% vs. 39.1%; p = 0.022). A similar effect of LYS was not seen in BA patients.. LYS, a mucolytic agent, has capability to improve the function of peripheral airways in patients with COPD, which leads to improvements of the patients' symptoms and QOL.

Topics: Aged; Aged, 80 and over; Asthma; Cross-Over Studies; Double-Blind Method; Dyspnea; Expectorants; Female; Humans; Male; Middle Aged; Muramidase; Nitric Oxide; Pulmonary Disease, Chronic Obstructive; Quality of Life; Spirometry; Sputum; Treatment Outcome

Lysozyme (mucopeptide N-acetyl-muramyl hydrolase) is widely used as a mucolytic and anti-inflammatory agent in Japan. We evaluated the effects of long-term lysozyme administration on COPD exacerbation.. In a 1-year, randomized, double-blind, placebo-controlled, parallel trial, patients with moderate-to-severe COPD and one or more episodes of COPD exacerbation in the previous year before enrollment were selected. Lysozyme (270 mg) or placebo was administered orally for 52 weeks as an add-on to the standard therapies such as bronchodilators. COPD exacerbation, pulmonary function, and COPD assessment test scores were analyzed. An exacerbation was defined as worsening of more than one symptom of COPD (cough, sputum volume, purulent sputum, or breathlessness) leading to a change in medication. The primary endpoint was exacerbation rate.. A total of 408 patients were randomly assigned to the lysozyme and placebo groups. The baseline characteristics were similar between the two groups. The exacerbation rate was not significantly different between the two groups (1.4 vs 1.2; P=0.292, Poisson regression). However, a subgroup analysis showed that lysozyme might reduce exacerbation rate in patients with airway-dominant phenotype (1.2 vs 1.6). Moreover, the median time to first exacerbation was longer in patients with airway-dominant phenotype in the lysozyme group than that in the placebo group. The levels of improvement in forced expiratory volume in 1 second and COPD assessment test scores were not statistically different between the groups, but were always greater in the lysozyme group than in the placebo group over the 52 weeks of the study.. The effects of using lysozyme as an add-on to standard COPD therapy were not significantly different compared with placebo and were insufficient to prevent COPD exacerbation.

Topics: Aged; Disease Progression; Double-Blind Method; Female; Humans; Male; Muramidase; Pulmonary Disease, Chronic Obstructive

Oral immunotherapy with inactivated non-typeable Haemophilus influenzae (NTHi) prevents exacerbations of chronic obstructive pulmonary disease, but the mechanism is unclear. The aim of this study was to determine the mechanism of protection. This was a placebo versus active prospective study over 3 months in 64 smokers. The active treatment was three courses of oral NTHi given at monthly intervals, followed by measurement of bacteriological and immunological parameters. The results can be summarized: (i) NTHi-specific T cells increased in the placebo treatment group over time (P<0.05); (ii) the T cell response in the oral NTHi group started earlier than that in the placebo group (P<0.05); and (iii) serum NTHi-specific immunoglobulin (Ig)G had significantly greater variation in the placebo group (P<0.0001). The increase in antibody in placebos over time correlated with exposure to live H. influenzae (P<0.05) determined from culture of gargles; (iv) reduction in saliva lysozyme over time (P<0.05) was detected only in the oral NTHi treatment group. These data are consistent with T cell priming of gut lymphoid tissue by aspiration of bronchus content into the gut, with oral immunotherapy augmenting this process leading to enhanced bronchus protection. The evidence for protection was a stable IgG antibody level through the study in the oral NTHi treatment group, contrasting with an increase in antibody correlating with exposure of the airways to H. influenzae in the placebo group. Saliva lysozyme was a useful biomarker of mucosal inflammation, falling after oral NTHi consistent with a reduction in the level of intralumenal inflammation.

Topics: Administration, Oral; Adolescent; Adult; Antibodies, Bacterial; Bronchitis; Carrier Proteins; Disease Progression; Female; Haemophilus influenzae; Haemophilus Vaccines; Humans; Immunity, Mucosal; Immunoglobulin G; Interferon-gamma; Lactoferrin; Male; Middle Aged; Muramidase; Nitric Oxide; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Saliva; Smoking; Sputum; T-Lymphocytes; Vaccines, Inactivated; Young Adult

Elastic fiber injury is an important process in the pathogenesis of chronic obstructive pulmonary disease (COPD), particularly with regard to the development of pulmonary emphysema. Damage to these fibers results in uneven distribution of mechanical forces in the lung, leading to dilatation and rupture of alveolar walls. While the role of various enzymes and oxidants in this process has been well-documented, we propose that a previously unsuspected agent, lysozyme, may contribute significantly to the changes in elastic fibers observed in this disease. Studies from our laboratory have previously shown that lysozyme preferentially binds to elastic fibers in human emphysematous lungs. On the basis of this finding, it is hypothesized that the attachment of lysozyme to these fibers enhances their susceptibility to injury, and further impairs the transfer of mechanical forces in the lung, leading to increased alveolar wall damage and enhanced progression of COPD. The hypothesized effects of lysozyme are predicated on its interaction with hyaluronan (HA), a long-chain polysaccharide that is found in close proximity to elastic fibers. By preventing the binding of HA to elastic fibers in COPD, lysozyme may interfere with the protective effect of this polysaccharide against enzymes and oxidants that degrade these fibers. Furthermore, the loss of the hydrating effect of HA on these fibers may impair their elastic properties, greatly increasing the probability of their fragmentation in response to mechanical forces. The proposed hypothesis may explain why the content of HA is significantly lower in the lungs of COPD patients. It may also contribute to the design of clinical trials involving the use of exogenously administered HA as a potential treatment for COPD.

Topics: Biomechanical Phenomena; Elastic Tissue; Humans; Hyaluronic Acid; Models, Biological; Muramidase; Pulmonary Alveoli; Pulmonary Disease, Chronic Obstructive

Pathogenic bacteria colonize the airways of 30% to 40% of patients with COPD and cause approximately 50% of exacerbations. New strains of nontypeable Haemophilus influenzae (NTHI) and Moraxella catarrhalis are associated with exacerbations. Antimicrobial protein/peptides (AMPs) play important roles in innate lung defense against pathogens. To our knowledge, the changes in AMP baseline levels in respiratory secretions during bacterial colonization and exacerbation have not been described. The objective of this study was to elucidate the effects of the acquisition of a new strain of pathogenic bacteria on the airway levels of AMPs in patients with COPD.. One hundred fifty-three samples from 11 patients were selected from COPD sputum samples collected prospectively over 6 years. Samples were grouped as culture-negative (no pathogenic bacteria), colonization, and exacerbation due to new strains of NTHI and M catarrhalis. Levels of lysozyme, lactoferrin, LL-37, and secretory leukocyte protease inhibitor (SLPI) were measured by enzyme-linked immunosorbent assay and compared among groups by paired analysis.. Compared with baseline, sputum lysozyme levels were significantly lower during colonization and exacerbation by NTHI (P = .001 and P = .013, respectively) and M catarrhalis (P = .007 and P = .018, respectively); SLPI levels were lower with exacerbation due to NTHI and M catarrhalis (P = .002 and P = .004, respectively), and during colonization by M catarrhalis (P = 032). Lactoferrin levels did not change significantly; LL-37 levels were higher during exacerbation by NTHI and M catarrhalis (P = .001 and P = .018, respectively).. Acquisition of NTHI and M catarrhalis is associated with significant changes in airway levels of AMPs, with larger changes in exacerbation. Airway AMP levels are likely to be important in pathogen clearance and clinical outcomes of infection in COPD.

Topics: Aged; Aged, 80 and over; Antimicrobial Cationic Peptides; beta-Defensins; Cathelicidins; Disease Progression; Female; Haemophilus Infections; Haemophilus influenzae; Humans; Inflammation; Lactoferrin; Male; Middle Aged; Moraxella catarrhalis; Moraxellaceae Infections; Muramidase; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Secretory Leukocyte Peptidase Inhibitor; Sputum