Bacterial tracheobronchitis. A rare cause of adult airway stenosis

Bacterial tracheobronchitis is a rare cause of airway stenosis in adults. This report describes a 73-year-old woman with a recent history of polysialadenitis, who presented with severe airway obstruction due to infection and stenosis of tracheal and bronchial tissue. Tissue culture of the bronchial mucosa showed growth of methicillin resistant Staphylococcus epidermidis (MRSE). Sputum culture showed growth of MRSE, Pseudomonas aeruginosa, Enterobacter cloacae and Enterococcus faecalis ; the same organisms were cultured from the salivary glands. Tracheostomy and antibiotic therapy were effective in controlling the disease.     

The role of airway secretions in COPD--clinical applications

It has been established that mucus hypersecretion and decreased mucus clearance contribute to the morbidity of chronic obstructive pulmonary disease (COPD). Indeed, the classic definition of chronic bronchitis relies on determining the frequency and duration of sputum expectoration. Despite the well recognized importance of this symptom, there are few therapies routinely used to decrease the sputum production or to improve clearance. There are fewer well conducted clinical trials of existing medications and this has led many regulatory agencies, notably the Food and Drug Administration (FDA), to refuse to register these medications or approve their sale. Similarly, airway clearance devices and chest physical therapy have not been well studied in COPD. Carefully conducted studies of interventions to improve airway clearance, similar to those done in cystic fibrosis (CF), may help us to identify effective therapies and possibly novel diagnostic tests for the management of COPD.     

Functions of proteins and lipids in airway secretions.

Proteins and lipids synthesized by airway secretory cells or transudated are active components in the protection of respiratory epithelium. Proteins and ions are involved in the control of mucus hydration. Secretory proteins, such as secretory immunoglobulin A (IgA), transferrin and lysozyme, participate in the airway antibacterial defence. Other biochemical components found in secretions, such as anti-inflammatory and antioxidant agents as well as antiproteases, contribute significantly to the protection of the underlying epithelium.     

Hydrogen peroxide-scavenging properties of normal human airway secretions

To examine the antioxidant capacity of normal human airway secretions and to characterize its molecular components, tracheal lavages were obtained from eight patients intubated for elective surgery and free of lung disease. These samples (20 microl, approximately 6.8 microg of protein) scavenged 0.57 +/- 0.09 nmol of added 0.96 nmol hydrogen peroxide (H2O2) within 10 minutes at room temperature (n = 8). The scavenging activity was inhibited 60 +/- 4% by azide (an inhibitor of heme-containing peroxidases and catalase) and 42 +/- 9% by dapsone (an inhibitor of lactoperoxidase). Mercaptosuccinic acid (an inhibitor of glutathione peroxidase) did not significantly inhibit H2O2 scavenging by these secretions. Fourfold diluted secretions showed only nonenzymatic scavenging activity, but the addition of thiocyanate to these samples (0.4 mM; substrate for lactoperoxidase) restored their ability to scavenge H2O2. The addition of reduced glutathione (8 microM) only enhanced nonenzymatic scavenging activity. These data provide evidence that multiple enzymatic and nonenzymatic systems coexist in human airway secretions that contribute to H2O2 scavenging. It appears, however, that H2O2 is mainly consumed by the lactoperoxidase system.     

Airway secretions influence upper airway patency in the rabbit

The hypothesis tested in these experiments was that the properties of the upper airway mucosal surface may be important in reopening of the closed airway, and that mucosal surface properties may depend on airway secretions. The intraluminal pressures required to close and reopen the upper airways were measured in the isolated upper airways of anesthetized rabbits. Atropine (0.1 mg/kg i.v.), given to reduce the volume of upper airway secretions, had no effect on closing or on reopening pressures. Stimulation of upper airway secretions in 6 animals with methacholine (0.2 mg/kg subcutaneously) changed closing pressures from -10.63 +/- 0.57 to -16.91 +/- 0.60 cm H2O (p less than 0.05) but made the airway less likely to reopen, changing reopening pressures from -3.45 +/- 0.48 to -2.12 +/- 0.39 cm H2O (p less than 0.04), and caused frequent failure of the airway to reopen spontaneously. Filling the upper airways with saline to mimic the hydrostatic forces present in the mucus-filled airway caused both closing and reopening pressures to become more negative. We conclude that reopening pressure is influenced by the secretions lining the airway surface, and, therefore, that airway closure and airway reopening may be substantially independent.     

Control and modulation of airway epithelial cells and their secretions

Information on the control and modulation of airway epithelial cells and their secretion is obtained by three techniques: 1) in vivo studies of animal models of disease, 2) in vitro studies by organ culture of human and animal model airways, and 3) chemical analysis of human and animal bronchial secretion. The contribution of each of these techniques is described in this paper, including recent or new information. In vivo models of mucous hypersecretion can be produced by irritants, infection, and drugs more quickly than previously expected. In the rat, beta 1 and beta 2 receptors are present with evidence of different activity in various airway regions. Organ culture studies combine autoradiographic analysis of cell activity with chemical analysis of secretory product, and describe inhibitory effect of new agents such as VIP. The application of density-gradient ultracentrifugation gives total recovery of undegraded macromolecules from bronchial mucus; it is now possible to recover mucous glycoprotein of molecular weight larger than that previously isolated. The organ culture studies and density-gradient ultracentrifugation studies indicate that a proteoglycan is a significant constituent of total bronchial secretion. Differences between diseases are emerging in the macromolecular partitioning between sol and gel obtained at 160,000 X g, a higher speed than that previously applied systematically in such studies.     

Characterization of masked specific proteinase inhibitor from bronchial secretions in purulent sputum as complex with leucocytic proteinases

By gelfiltration and ionexchange chromatography, proteinase bound proteinase inhibitor, specific for mucous membranes was isolated from purulent sputum of patients with obstructive airway diseases. The isolated material contains 25% complexed inhibitor. The complex interacts with specific anti-inhibitor-serum and anti-inter-alpha-trypsininhibitor-serum. With anti-leucocytic-proteinase-serum an interaction is observed, too. The proteinasepart of the complexed inhibitor therefore is a leucocytic proteinase.     

Uric acid is a major antioxidant in human nasal airway secretions.

Airway mucosal surfaces are potentially subjected to a variety of oxidant stresses. Airway submucosal glands secrete a variety of compounds that may protect the airways from injury. Cholinergically induced nasal submucosal gland secretion has recently been found to contain a low molecular weight nasal antioxidant. In this report, the isolation and identification of this nasal secretory antioxidant are described. Concentrated, cholinergically induced human nasal secretions were fractionated through a 10-kDa sieve and subjected to DEAE anion-exchange chromatography. Fractions containing antioxidant activity were subjected to gel filtration with Bio-Gel P-2 gel (resolution range, 200-2000 Da). The resultant antioxidant fractions were then desalted by gel filtration over the same column equilibrated in HPLC-grade water, yielding only a single peak with antioxidant activity. The absorption spectrum of the purified antioxidant revealed peaks at 238 and 292 nm at pH 7. These peaks shifted to 230 and 280 nm in 0.1 M HCl and 226 and 296 nm in 0.1 M NaOH. Sodium borohydride reduction of the antioxidant had no effect on the UV absorption, whereas platinum-catalyzed hydrogenation ablated all absorption peaks. Uric acid had identical absorption peaks and showed the same chromatographic behavior as the nasal antioxidant activity on both gel filtration and DEAE columns. Uricase (which degrades uric acid) metabolized both uric acid and the purified antioxidant. Uric acid was shown to have antioxidant activity at concentrations greater than 1.5 microM. These data indicate that nasal secretions contain uric acid that serves as an antioxidant.     

Density gradient analysis of secretions produced in vitro by human and canine airway mucosa: identification of lipids and proteoglycans in such secretions

Human and canine airway mucosal explants synthesize and secrete high molecular weight glycoconjugates, incorporating 14C-glucosamine, a radioactive precursor to epithelial glycoprotein. Our examination of secretions produced by several individual specimens, however, did not reveal epithelial glycoprotein of typical buoyant density (1.5 g/ml in CsBr); only a high-density component with features of glycoprotein and proteoglycan. To provide sufficient material for characterization, secretions from several specimens of human and canine explants were separately pooled and subjected to DGU in CsBr. After removal of lipids and proteins, the glycoconjugates were recovered into five fractions of different density. 14C-glucosamine had been incorporated in all five fractions. Fractions 1-4 together accounted for 88% of the radiolabel but gas chromatography indicated that none of these contained epithelial glycoprotein. Their amino acid compositions were similar to those of proteoglycans and electrophoresis confirmed the presence of chondroitin sulfates A, B, C, heparan sulfate and hyaluronic acid. Sugars typical of epithelial glycoprotein were identified only in the glycoconjugate subfraction 5 of lowest density (and also lowest in yield) in which glycosaminoglycans were also identified. By addition of radioactive precursors, 14C acetate, 14C palmitate and 14C mevalonic acid to the culture medium and autoradiography of the secreted lipids we have shown that the tracheal explants actively synthesize lipids. Lipids accounted for a high proportion, almost half by weight, of the explant secretion. While neutral and phospholipids predominate, glycolipids were also identified.     

Inflammatory profile in nasal secretions of infants hospitalized with acute lower airway tract infections

OBJECTIVE: The aim of this study was to determine whether the regulatory immune response (interleukin (IL)-10 response) differed between children hospitalized with acute respiratory infections and wheezing. METHODOLOGY: Infants with signs and symptoms of acute viral respiratory infection, admitted during winter 2000 to Princess Margaret Hospital for Children, Perth, WA, Australia, were enrolled in this study. Nasopharyngeal aspirates were collected in the first 48 h of admission. Total cell count and differential cell counts were assessed. Samples were tested for the presence of respiratory viruses. The concentrations of the anti-inflammatory cytokine IL-10, and pro-inflammatory cytokines IL-8, interferon-gamma, and IL-11 were determined by ELISA. RESULTS: Children with acute bronchiolitis (AB; n = 36), recurrent wheeze (RW; n = 17) and upper respiratory infection (URI; n = 18) were enrolled. Respitory syncytial virus was the most commonly detected virus in all groups. IL-10 concentrations were significantly increased in AB (median, 0.019 ng/mL) when compared to URI (median, 0.006 ng/mL) or to RW (median, 0.007 ng/mL; P < 0.05). Neutrophils were the predominant cells in the cytological analysis in all subjects. CONCLUSION: These data argue that host-response factors are important in determining the clinical phenotype, independent of the causative virus.     

The role of airway secretions in COPD: pathophysiology, epidemiology and pharmacotherapeutic options

Often considered an aggravating but otherwise benign component of chronic obstructive pulmonary disease (COPD), airway mucus hypersecretion is now recognised as a potential risk factor for an accelerated loss of lung function in COPD and is a key pathophysiological feature in many patients, particularly those prone to respiratory tract infection. Consequently, it is important to develop drugs that inhibit mucus hypersecretion in these susceptible patients. Conventional therapy including anticholinergics, beta2-adrenoceoptor agonists, alone or in combination with corticosteroids, mucolytics and macrolide antibiotics are not entirely or consistently effective in inhibiting airway mucus hypersecretion in COPD. Novel pharmacotherapeutic targets are being investigated, including inhibitors of nerve activity (e.g., BK(Ca) channel activators), tachykinin receptor antagonists, epoxygenase inducers (e.g., benzafibrate), inhibitors of mucin exocytosis (e.g., anti-MARCKS peptide and Munc-18B blockers), inhibitors of mucin synthesis and goblet cell hyperplasia (e.g., EGF receptor tyrosine kinase inhibitors, p38 MAP kinase inhibitors, MEK/ERK inhibitors, hCACL2 blockers and retinoic acid receptor-alpha antagonists), inducers of goblet cell apoptosis (e.g., Bax inducers or Bcl-2 inhibitors), and purinoceptor P(2Y2) antagonists to inhibit mucin secretion or P(2Y2) agonists to hydrate secretions. However, real and theoretical differences delineate the mucus hypersecretory phenotype in COPD from that in other hypersecretory diseases of the airways. More information is required on these differences to identify therapeutic targets pertinent to COPD which, in turn, should lead to rational design of anti-hypersecretory drugs for specific treatment of airway mucus hypersecretion in COPD.     

Assessing the effects of racemic and single-enantiomer albuterol on airway secretions in long-term intubated patients

OBJECTIVE: In vitro data suggest that the S-enantiomer of albuterol can induce mucociliary dysfunction. This clinical study assesses the clinical significance of standard doses of the S-enantiomer on airway secretions in long-term intubated patients by comparing a racemic formulation of albuterol, an R-enantiomer formulation, and normal saline solution. DESIGN: A placebo-controlled crossover study. PATIENTS: Fourteen stable intubated patients with a median duration of intubation of 21 months and a median age of 72 years. SETTING: Long-term ventilator unit in skilled nursing facility. INTERVENTIONS: Following a 2-week washout period during which regularly scheduled beta2-agonists were discontinued, tracheal aspirates were collected for 4 h/d for a 5-day period to establish baseline values, and the patients were then randomized in crossover manner to each of three nebulized treatments: normal saline solution, racemic albuterol, and R-albuterol. Each treatment was administered three times daily for 5 days, followed by a 2-day washout. MEASUREMENTS: Tracheal aspirates were analyzed for volume, sodium, chloride, bicarbonate, interleukin (IL)-8, IL-1beta, soluble intercellular adhesion molecule, and tumor necrosis factor-alpha. RESULTS: There were no consistent significant differences among the three treatment periods either in terms of volume of secretions or in the concentrations of the electrolytes or the inflammatory indexes. However, all three treatments, including saline solution, were associated with increased secretion volume after the first dose, but this effect was not apparent on subsequent doses. CONCLUSION: There were no significant differences between racemic albuterol and R-albuterol observed in this study for any of the parameters studied, suggesting that the S-enantiomer does not adversely affect airway secretions at recommended doses. In addition, the routine administration of nebulized beta(2)-sympathomimetic agonists to stable patients undergoing prolonged intubation, for the sole purpose of changing the volume and composition of secretions of airway secretions, is not supported by the results of this study.     

Role of Proteases and Antiprotease in the Etiology of Chronic Pancreatitis

Background/Aim:

Chronic pancreatitis (CP) is the progressive and irreversible destruction of the pancreas characterized by the permanent loss of endocrine and exocrine function. Trypsin, the most important digestive enzyme plays a central role in the regulation of all other digestive enzymes. Chymotrypsin, an endopeptidase hydrolyzes peptides at amino acids with aromatic side chains. Alpha-1-antitrypsin is a principal antiprotease which protects the mucosal tissue from the proteolytic effects of trypsin and chymotrypsin by the formation of molar complexes. The present study is aimed at examining the role of proteases (trypsin and chymotrypsin) and anti-protease (α1-anti-trypsin) in the etiopathogenesis of chronic pancreatitis.

Patients and Methods:

A total of 90 CP patients and 110 age and sex matched controls were considered for the study. Serum trypsin, chymotrypsin and α1-anti-trypsin levels were determined prospectively in CP patients and compared to healthy controls as described previously.

Results:

The mean activity of trypsin were found to be increased in CP patients (X ± SD = 0.82 ± 0.838) in comparison to normal control group (X ± SD = 0.55 ± 0.328), (P = 0.001). Chymotrypsin activity were also found to be elevated in CP patients (X ± SD = 0.63 ± 0.278) in comparison to control group (X ± SD = 0.39 ± 0.295), (P = 0.0001). The mean α-1-anti-trypsin activity were found to be lowered in CP patients (X ± SD = 0.42 ± 0.494) in comparison to control group (X ± SD = 0.67 ± 0.465), with the variation being significant (P = 0.0003).

Conclusion:

The findings suggest an imbalance in the synthesis and degradation of proteolytic enzymes and antiprotease indicating an altered aggressive and defensive role in the pathogenesis of chronic pancreatitis.     

Improved activity of an actin-resistant DNase I variant on the cystic fibrosis airway secretions

In cystic fibrosis (CF), actin and DNA originating from inflammatory cells contribute to the thickness of airway secretions. Actin can bind to DNA-rich fibers and potently inhibit the enzymatic activity of rhDNase. The in vitro effects of the actin-resistant rhDNase variant (A114R) were analyzed and compared with those of the wild-type rhDNase. Frozen and thawed CF airway secretions were incubated for 30 min with different concentrations (0.1, 0.5, 1, 5, or 10 microg/ml) of either actin-resistant rhDNase or wild-type rhDNase. We observed that both the wild-type and the actin-resistant rhDNase significantly decreased (p < 0.05 and p < 0.001, respectively) the airway secretion viscosity. The decrease in airway secretion viscosity was significant even at low concentrations (0.1 microg/ml) of the actin-resistant variant. Incubation with the actin-resistant variant resulted in a significant decrease (p < 0.02) of the airway secretion contact angle and cough transport. A significantly higher (p < 0.01) increase in contact angle and cough transport of airway secretions was observed at 10 microg/ml with the actin-resistant variant as compared with the wild-type rhDNase. The present study had demonstrated that the actin-resistant rhDNase variant (A114R) has an enhanced capacity to improve the physical properties and cough transport of airway secretions from patients with cystic fibrosis.     

Small airway function improvement after smoking cessation in smokers without airway obstruction

OBJECTIVE: Studying smokers with normal spirometry requires monitoring tools of the peripheral lung. A validated multiple breath washout technique was used to assess possible recovery of smoking-induced small airway malfunction in acinar and conductive lung zones. METHODS: Eighty-seven smokers with a smoking history of at least 10 pack-years but absence of spirometric airflow obstruction were invited for assessment of lung function and small airway function at baseline and after 1 wk, 3 mo, 6 mo, and 12 mo of smoking cessation. A control group of 16 persistent smokers was studied at the same time intervals. MEASUREMENTS AND MAIN RESULTS: Of the 87 smokers, 66, 32, 28, and 21% successfully ceased smoking for 1 wk, 3 mo, 6 mo, and 12 mo, respectively. Lung function parameters remained essentially unaffected by smoking cessation. Ventilation heterogeneity showed transient improvements after 1 wk in the acinar lung compartment with a return to baseline afterwards. By contrast, there were persistent improvements in the conductive airway compartment; for example, smokers who successfully quit smoking for 12 mo (n=18) showed a 30 and 42% reduction of conductive airways abnormality after 1 wk and 1 yr, respectively. CONCLUSIONS: Smokers with early signs of small airway malfunction who successfully quit smoking show sustained improvements of conductive airway malfunction. In contrast, acinar airway malfunction quickly returns to baseline after a transient improvement.