Effects of MMP-9 inhibition by doxycycline on proteome of lungs in high tidal volume mechanical ventilation-induced acute lung injury.

BACKGROUND: Although mechanical ventilation (MV) is a major supportive therapy for patients with acute respiratory distress syndrome, it may result in side effects including lung injury. In this study we hypothesize that MMP-9 inhibition by doxycycline might reduce MV-related lung damage. Using a proteomic approach we identified the pulmonary proteins altered in high volume ventilation-induced lung injury (VILI). Forty Wistar rats were randomized to an orally pretreated with doxycycline group (n = 20) or to a placebo group (n = 20) each of which was followed by instrumentation prior to either low or high tidal volume mechanical ventilation. Afterwards, animals were euthanized and lungs were harvested for subsequent analyses. RESULTS: Mechanical function and gas exchange parameters improved following treatment with doxycycline in the high volume ventilated group as compared to the placebo group. Nine pulmonary proteins have shown significant changes between the two biochemically analysed (high volume ventilated) groups. Treatment with doxycycline resulted in a decrease of pulmonary MMP-9 activity as well as in an increase in the levels of soluble receptor for advanced glycation endproduct, apoliporotein A-I, peroxiredoxin II, four molecular forms of albumin and two unnamed proteins. Using the pharmacoproteomic approach we have shown that treatment with doxycycline leads to an increase in levels of several proteins, which could potentially be part of a defense mechanism. CONCLUSION: Administration of doxycycline might be a significant supportive therapeutic strategy in prevention of VILI.

Lung function and farm size predict healthy worker effect in swine farmers.

BACKGROUND: Swine farmers are exposed to a number of airborne contaminants associated with respiratory ill health. OBJECTIVES: To examine the factors associated with healthy worker effect in the swine industry from a longitudinal follow-up of farmers at 4 years and 13 years. DESIGN: A prospective study of swine farmers and nonexposed rural residents was conducted using similar questionnaires and same spirometer at each time point. RESULTS: In the original observations in 1990/1991, we studied 302 swine farmers and 261 nonfarming control subjects. Four years later in 1994/1995, 217 swine farmers and 171 nonfarming control subjects of the original group participated again. In 2003/2004, 163 swine farmers and 118 control subjects were retested. Of the 163 swine farmers, 52 remained active swine farmers and 111 were no longer swine farming, thus providing the opportunity to evaluate work continuity in the industry. Among farmers studied in 2003/2004, mean values for percentage of predicted FEV(1)/FVC ratio and forced expiratory flow between 25% and 75% of FVC were lower in those who had quit swine farming compared to those still swine farming and nonfarming control subjects. The herd size in the barn at baseline in 1990/1991 and at interim follow-up in 1994/1995 was a significant predictor of quitting swine farming. In addition, percentage of predicted FEV(1)/FVC at the interim observation was a significant predictor of quitting swine farming. CONCLUSIONS: There is a significant healthy worker effect among swine farmers. The continuation of work in the facilities may be predicted by herd size and interim lung function.

A comparison of 2 methods of continuous aerosol administration during methacholine challenge testing.

BACKGROUND: Exposure to the bronchoconstricting agent methacholine is a potential hazard to technical staff during methacholine challenge testing, which remains a useful and frequently performed test. There are several methods of performing the test. One of the 2 methods listed in the American Thoracic Society's guidelines is the 2-min tidal-breathing method. The methacholine can be inhaled using one of several methods. The loosely-fitting-mask method is likely to produce more contamination of the local environment than a filtered exhalation system. METHODS: We tested 2 variations of the tidal-breathing method of measuring the methacholine provocational concentration (PC(20), the dose that produces a 20% decrease in forced expiratory volume in the first second). One involved use of the open-mask technique and the other a T-piece-and-filter system that precluded the release of methacholine-containing droplets into the environment. We performed duplicate methacholine challenge tests with 10 subjects who had a wide range of PC(20). The tests were done in random order, and each subject performed one test using the mask and one using the T-piece/filter system. RESULTS: With the mask system the geometric mean PC(20) was 4.7 mg/mL, versus 5.1 mg/mL with the T-piece-filter system (p = 0.36). These values are very close and would not be substantially different clinically. CONCLUSION: The 2 methods are equivalent, and the low cost of the products used in the T-piece/filter method makes it suitable for reducing technician exposure to methacholine, using potentially completely disposable components.

The American Thoracic Society's spirometric criteria alone is inadequate in asthma diagnosis.

BACKGROUND: The diagnosis of asthma is based on clinical symptoms, physical examination and pulmonary function tests, and can be very challenging. Most patients with asthma have a significant postbronchodilator response on spirometry indicating airway hyperresponsiveness. However, having a significant bronchodilator response by itself is not diagnostic of asthma. The definition of a 'significant' response has also been controversial. Many respirologists use the American Thoracic Society (ATS) postbronchodilator response criteria of 12% (provided it is 200 mL or greater) improvement in forced expiratory volume in 1 s (or forced vital capacity) from the baseline spirometry. METHODS: In the present study, 644 patients who met the ATS criteria for a significant postbronchodilator spirometric response were retrospectively reviewed. The staff respirologist's diagnosis of asthma, based on all clinical and pulmonary function data, was used as the standard for the diagnosis of asthma. RESULTS: Relying on spirometric criteria alone was inadequate in asthma diagnosis because only 54.7% of 310 patients who met the ATS bronchodilator response criteria were thought to have clinical asthma. Increasing the postbronchodilator percentage improvement from the ATS criteria only marginally improved diagnostic specificity and resulted in a decline in sensitivity. CONCLUSIONS: The results of the present study further emphasize the need to use spirometric criteria as a guide but not as an unimpeachable gold standard with which to make a diagnosis of asthma. The diagnosis of asthma depends on expert physician correlation of patient history, physical examination and pulmonary function test results.

Difference between dosimeter and tidal breathing methacholine challenge: contributions of dose and deep inspiration bronchoprotection.

BACKGROUND: Two bronchoprovocation methods are widely used. Compared to the tidal breathing method, the dosimeter method delivers approximately half the dose and involves five deep inhalations. Both the lower dose and the bronchoprotective deep inhalations contribute to the lesser airway response of the dosimeter. OBJECTIVE: To determine the relative role of dose and deep inspiration in the difference between the two methods. METHODS: Subjects with asthma (n = 24) underwent three methacholine challenges: a dosimeter challenge, a 2-min tidal breathing challenge (twice the dose), and a modified 2-min tidal breathing challenge (twice the dose plus five deep inhalations). RESULTS: The dosimeter method produced a nonsignificantly lower response than the modified tidal breathing method (p = 0.14). Both deep inhalation methods produced significantly less response than did the standard tidal breathing method (p = 0.011). In the 12 subjects with the most mild airway hyperresponsiveness (AHR), the differences between the deep inhalation method and the tidal breathing method were greater (p = 0.007). By contrast, deep inhalations produced no effect in the 12 subjects with greater AHR; the two tidal breathing methods produced identical results, while the dosimeter produced less response than either (p = 0.033). Six current asthmatics with mild airway responsiveness (tidal breathing method) had negative dosimeter methacholine challenge results. CONCLUSIONS: In subjects with moderate airway responsiveness, the difference between the methods is due to the difference in dose, whereas in subjects with mild AHR, deep inhalations had a large effect overwhelming the dose effect and producing false-negative methacholine challenge results in 25% of the subjects.

Respiratory symptoms and lung function in poultry confinement workers in Western Canada.

OBJECTIVE: To determine whether poultry production methods impact respiratory health, and whether poultry farmers have more respiratory symptoms and lower lung function than comparison control groups. DESIGN: Cross-sectional study. SETTING: Provinces of Saskatchewan, Alberta and Manitoba during the winters of 1997 to 1999. POPULATION: Three hundred three poultry workers, 241 grain farmers and 206 nonfarming control subjects were studied. Poultry workers were further classified according to the poultry housing type in which they worked, ie, workers who worked with poultry raised on the floor (floor-based operations), which included broiler/roaster, broiler/breeder and turkey operations (n=181), and workers who worked with poultry raised in a caged setting (cage-based operations), which included egg operations (n=122). INTERVENTIONS: Subjects completed a respiratory health questionnaire, which included questions on the poultry operation and work habits, and participated in lung function testing. MAIN RESULTS: Overall, this study indicated that poultry workers report greater prevalences of current and chronic respiratory symptoms than control populations, and that the type of production method (cage-based versus floor-based) appears to influence the prevalence of respiratory symptoms and lung function values. Workers from cage-based operations report greater prevalences of current cough and wheeze, as well as lower mean values for forced expiratory volume in the first second (FEV1), forced expiratory flow at 25% to 75% of vital capacity (FEF25-75) and FEV1/FVC than workers from floor-based facilities. Workers from cage-based facilities also reported greater prevalences of current and chronic cough and phlegm, as well as significantly lower FEF25-75 and FEV1/FVC values than nonfarming control subjects. Furthermore, grain farmers had lower FVC and FEV1 values than nonfarmers. CONCLUSIONS: The results suggest that the type of poultry production system (ie, floor- versus cage-based) appears to have an effect on the respiratory response of workers from these facilities. Further studies are required to understand the physiological mechanisms of respiratory dysfunction and the relationships concerning workplace exposure among poultry workers.

Excess longitudinal decline in lung function in grain farmers.

Workers in intensive agricultural operations are exposed to dust and endotoxin that are associated with respiratory effects. The authors investigated the longitudinal changes in lung function in male grain farmers. In this study, male grain farmers (n = 263) and male nonfarming control subjects (n = 261) studies initially in 1990/91 were followed-up in 1994/95 and 2003/04. After controlling for potential confounders, grain farmers had an excess annual decline of 9.2 ml/year (95% confidence interval [CI]: 2.7, 15.8, p = .006) in forced vital capacity (FVC) in comparison to control. Long-term exposure to grain dust and other substances in lifetime grain farmers results in progressive loss in lung function.

Dosimeter methacholine challenge: comparison of maximal versus submaximal inhalations.

BACKGROUND: Deep inhalation has bronchodilating and bronchoprotective effects, particularly in subjects who are normal or have mild airway hyperresponsiveness (AHR). We have anecdotally observed that the 5 breath to total lung capacity (TLC) dosimeter method reduced the response to methacholine in some subjects with mild AHR. OBJECTIVE: To compare prospectively submaximal inhalations with TLC inhalations during the dosimeter methacholine challenge. METHODS: Sixteen subjects with asthma and a methacholine PC 20 <8 mg/mL performed 2 methacholine challenges in random order; the standard dosimeter method was compared with a modified dosimeter challenge in which methacholine inhalations were performed to approximately 50% to 60% below TLC. RESULTS: The standard methacholine challenge PC 20 was almost twice that obtained with the modified submaximal inhalation method (geometric mean PC 20, 5.2 mg/mL vs 2.8 mg/mL, respectively; P = 0.0216). In the 5 subjects with the mildest AHR, there was a 2.5-fold to 14-fold difference in PC 20 between methods. The standard (full TLC) PC 20 s were falsely negative (>16 mg/mL) in these 5 subjects with current asthma, 4 of whom required inhaled corticosteroids. CONCLUSION: A submaximal inhalation dosimeter methacholine challenge results in a significantly lower PC 20 compared with the standard 5-breath dosimeter method. This effect is limited to the mildly responsive group, probably because of the bronchoprotective effect of the deep inhalation during the standard method, and results in false-negative tests in some subjects.