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MPO deficiency

Myeloperoxidase deficiency is a genetic disorder featuring deficiency of myeloperoxidase. It presents with immune deficiency (especially candida albicans infections), although many people with MPO deficiency do not have a severe phenotype and do not have infections.

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Its Relationship to Colonizing Microbial Load and [[Alpha].sub.1]-Antitrypsin Deficiency
From CHEST, 5/1/00 by Robert A. Stockley

Neutrophil elastase is capable of generating many of the features of chronic bronchial disease. In patients with COPD, airways inflammation with neutrophil recruitment and elastase release is positively correlated with colonizing bacterial load in the stable clinical state (p [is less than] 0.0005). In addition, [[Alpha].sub.1]-antitrypsin deficiency is associated with a greater neutrophil load, higher elastase activity, leukotriene-[B.sub.4] concentration, and serum protein leak than matched patients without deficiency (p [is less than] 0.005). These data confirm an effect of bronchial colonization on airways inflammation in COPD and indicate the role of [[Alpha].sub.1]-antitrypsin in its modulation.

(CHEST 2000; 117:291S-293S)

Key words: [[Alpha].sub.1]-antitrypsin deficiency; bacteria; COPD; inflammation

Abbreviations: [[Alpha].sub.1]-AT = [[Alpha].sub.1]-antitrypsin; [LTB.sub.4] = leukotriene [B.sub.4]; MPO = myeloperoxidase; NE = neutrophil elastase; SLPI = secretory leukoproteinase inhibitor

The presence of bronchial disease is often a feature of patients with COPD. It is associated with inflammation, as indicated by the presence of increased numbers of neutrophils,[1] reduction in mucociliary clearance, mucus gland hyperplasia, and epithelial damage,[2] all of which may facilitate bacterial colonization.

Neutrophil elastase (NE) has been shown to produce many of the features of bronchial disease, including the generation of mucus gland hyperplasia, active mucus secretion, a decrease in ciliary beat frequency, and epithelial damage. In addition, there are other changes to key host defenses within the airway generated by this enzyme, all of which may result in a facilitation of bacterial colonization. This, in turn, will drive inflammation and can result in the perpetuation of airways inflammation, damage, and continued bacterial colonization.[3]

Although these features have been studied extensively in vitro, there have been very few studies in man. In particular, the degree of inflammation and its relationship to any colonizing bacterial load is unknown. Furthermore, the role of [[Alpha].sub.1]-antitrypsin ([[Alpha].sub.1]-AT) in the protection of the airway has previously been considered to be of less importance than in the interstitium, because secretory leukoproteinase inhibitor (SLPI) is believed to be the major elastase inhibitor in the airway. The purposes of the current studies, therefore, were to assess airways inflammation and to determine the influence of the colonizing microbial load and the effect of [[Alpha].sub.1]-AT deficiency.


We studied 55 patients with chronic obstructive bronchitis, 64 patients with a similar degree of airflow obstruction related to [[Alpha].sub.1]-AT deficiency (phenotype Pi Z), and 43 patients with idiopathic bronchiectasis diagnosed by high-resolution CT scan. Sputum was collected over a 4-h period from rising from each patient, and an aliquot was removed and assessed for the colonizing microbial load as described previously.[4] The remaining sample was ultracentrifuged to obtain the sputum sol phase. These samples were stored at -70 [degrees] C until analyzed for the presence of myeloperoxidase (MPO; as a marker of neutrophil content); the activity of NE; the chemoattractants, interleukin-8, and leukotriene [B.sub.4] ([LTB.sub.4]); and finally the inhibitors [[Alpha].sub.1]-AT and SLPI and albumin. Serum was obtained at the same time for the measure of serum albumin to determine the sputum to serum albumin ratio as a measure of protein leakage. These methods and their validation have been described in detail elsewhere.[5]


Inflammation in the airway was clearly associated with the presence and size of colonizing microbial load as indicated by the positive correlations with MPO (r = 0.58; p [is less than] 0.0005), NE activity (r = 0.43; p [is less than] 0.0005), interleukin-8 (r = 0.67; p [is less than] 0.0001), [LTB.sub.4] (r = 0.48; p [is less than] 0.0005), sputum-serum albumin ratio (r = 0.43; p [is less than] 0.0005), and a negative correlation with SLPI (r = - 0.52; p [is less than] 0.0005). The relationship indicated a microbial threshold of [10.sup.6] cfu below which inflammation was present but low, but above which it was markedly enhanced and related to the size of the colonizing load (see Fig 1).


The studies indicated that patients with [[Alpha].sub.1]-AT had a greater degree of inflammation than chronic obstructive bronchitis patients without deficiency even when they were matched for smoking history, airflow obstruction, and bacterial load. The [[Alpha].sub.1]-AT-deficient patients had a greater sputum MPO concentration (p [is less than] 0.001); readily detectable and increased elastase activity (p [is less than] 0.001); [LTB.sub.4] (p [is less than] 0.005); and sputum-serum protein ratio (p [is less than] 0.001). In addition, the SLPI concentrations were reduced in [[Alpha].sub.1]-AT deficiency (p [is less than] 0.05).


The results presented here confirmed that subjects with chronic bronchial disease have inflammation present in their airways as indicated by the presence of neutrophils (quantified by the MPO concentration) and leakage of the serum protein albumin. It is well known that patients with chronic bronchial disease can be colonized with bacteria even in the stable clinical state.[6] The current data confirm that some patients are colonized and that the bacterial load may vary from [10.sup.5] to [is greater than] [10.sup.8] cfu/mL. Of importance, the degree of inflammation in the airway is dependent on the colonizing bacterial load. In the absence of bacteria or when bacterial load is [is less than or equal to] [10.sup.5] cfu/mL, inflammation is relatively low. However, as the colonizing load rises above [10.sup.6] organisms/mL, inflammation rises increasingly dependent on the size of the bacterial load. This first demonstration of such a change in human disease is consistent with previous animal model studies,[7] and suggests that such colonization is not a benign feature of patients with airways disease.

The data also confirm that [[Alpha].sub.1]-AT deficiency is associated with a greater degree of airways inflammation. It is conventionally believed that the major inhibitor of elastase in the airway is SLPI. However, patients with [[Alpha].sub.1]-AT deficiency have slightly reduced SLPI concentrations compared to subjects without deficiency. The mechanisms involved in the airways are clearly complex. Previous workers have suggested that an increase in [LTB.sub.4] in the lungs of patients with [[Alpha].sub.1]-AT deficiency is a direct result of failure to completely inactivate elastase in the airways.[8] The increased [LTB.sub.4] released results in neutrophil recruitment and hence delivery of more elastase to the airways. In our current study, in the presence of bronchial disease, patients with [[Alpha].sub.1]-AT deficiency have a greater amount of elastase activity in their secretions compared to nondeficient patients. In addition, the [LTB.sub.4] is high, as is neutrophil recruitment (indicated by the MPO concentration). The reduction in SLPI could be a direct effect of free NE activity in the airway, since this enzyme has been shown to reduced SLPI secretion by epithelial cells.[9] This may explain the lower SLPI concentrations found in the [[Alpha].sub.1]-AT-deficient subjects, and such a change would clearly facilitate the activity of the elastase. Finally, elastase activity has been shown to result in protein leakage across epithelial cells in vitro,[10] and this would be consistent with the increased sputum serum albumin ratio seen in the current studies as inflammation and elastase activity rise.

In summary, these observations provide further insights into bronchial inflammation and factors that may influence it. However, the true interrelationship of all these factors awaits the development of intervention studies with specific inhibitors.


[1] Pesci A, Balbi B, Majori M, et al. Inflammatory cells and mediators in bronchial lavage of patients with chronic obstructive pulmonary disease. Eur Respir J 1998; 12:380-386

[2] Stockley RA. The pathogenesis of chronic obstructive lung diseases: implications for therapy. Q J Med 1995; 88:141-146

[3] Stockley RA. The role of proteinases in the pathogenesis of chronic bronchitis. Am J Respir Crit Care Med 1994; 150(6 part 2):S109-S113

[4] Pye A, Stockley RA, Hill SL. Simple method for quantifying viable bacterial numbers in sputum. J Clin Pathol 1995; 48:719-724

[5] Hill AT, Bayley D, Stockley RA. The interrelationship of sputum inflammatory markers in patients with chronic bronchitis. Am J Respir Crit Care Med 1999; 160:893-898

[6] Monso E, Ruiz J, Rosell A, et al. Bacterial infection in chronic obstructive pulmonary disease: a study of stable and exacerbated out-patients using the protected specimen brush. Am J Respir Crit Care Med 1995; 152:1316-1320

[7] Onofrio JM, Toews GB, Lipscombe MF, et al. Granulocyte-alveolar-macrophage interaction in the pulmonary clearance of Staphylococcus aureus. Am Rev Respir Dis 1983; 127:335-341

[8] Hubbard RC, Fells G, Gadek J, et al. Neutrophil accumulation in the lungs in [[Alpha].sub.1]-antitrypsin deficiency: spontaneous release of leukotriene [B.sub.4] by alveolar macrophages. J Clin Invest 1991; 88:891-897

[9] Sallenave JM, Schulmann J, Crossly J, et al. Regulation of secretory leukocyte proteinase inhibitor (SPLI) and elastase specific inhibitor (ESI-elafin) in human airway epithelial cells by cytokines and neutrophilic enzymes. Am J Respir Cell Mol Biol 1994; 11:733-741

[10] Peterson MW, Walter ME, Nygaard SD. Effect of neutrophil mediators on epithelial permeability. Am J Respir Cell Mol Biol 1995; 13:719-727

(*) From the Department of Medicine (Drs. Stockley, Hill, and Hill), Queen Elizabeth Hospital, Birmingham B15 2TH, UK; and the University of Utah (Dr. Campbell), Salt Lake City, UT. Supported by a noncommercial educational grant from Bayer as part of the ADAPT Programme.

Correspondence to: Robert A. Stockley, DSc, MD, Department of Medicine, Queen Elizabeth Hospital, Birmingham B15 2TH, UK

COPYRIGHT 2000 American College of Chest Physicians
COPYRIGHT 2000 Gale Group

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