Oxygen Uptake and Lactate Kinetics in Patients with Chronic Obstructive Pulmonary Disease during Heavy Intensity Exercise: Role of Pedaling Cadence.

Oxygen uptake slow component ([Formula: see text]sc) is associated with lactate accumulation, likely a contribution of poorly oxidative muscle fibers. We aimed to test the hypothesis that higher muscle tension during slow pedaling rates would yield more prominent [Formula: see text]sc in healthy subjects, but not in COPD patients. Eight severe COPD patients and 8 age-matched healthy individuals performed 4 rest-heavy exercise transitions at 40 and 80 RPM. Work rates at the two cadences were balanced. Venous blood was sampled for measurement of lactate concentration at rest and every 2 minutes until the end of exercise. [Formula: see text] kinetics were analyzed utilizing nonlinear regression. [Formula: see text] phase II amplitudes at the two cadences were similar in both groups. In healthy individuals, [Formula: see text]sc was steeper at 40 than 80 RPM (46.6 ± 12.0 vs. 29.5 ± 11.7 mL/min2, p = 0.002) but not in COPD patients (16.2 ± 14.7 vs. 13.3 ± 7.6 mL/min2). End-exercise lactate concentration did not differ between cadences in either group. In healthy individuals, greater slow-cadence [Formula: see text]sc seems likely related to oxidative muscle fiber recruitment at higher muscular tension. COPD patients, known to have fast-twitch fiber predominance, might be unable to recruit oxidative fibers at high muscle tension, blunting [Formula: see text]sc response.

Allergic inflammation in the human lower respiratory tract affected by exposure to diesel exhaust.

To improve understanding of human health risks from exposure to diesel exhaust particles (DEP*), we tested whether immunologic effects previously observed in the human nose also occur in the lower airways. Our overall hypothesis was that cell influx and production of cytokines, chemokines, immunoglobulin E (IgE), and other mediators, which would be measurable in sputum and blood, occur in people with asthma after realistic controlled exposures to diesel exhaust (DE). In Phase 1 we tested for direct effects of DE in subjects with clinically undifferentiated mild asthma. In Phase 2 we tested whether DE exposure would exacerbate response to inhaled cat allergen in subjects with both asthma and cat sensitivity. The exposure facility was a controlled-environment chamber supplied with DE from an idling medium-duty truck with ultra-low-sulfur fuel and no catalytic converter. We exposed volunteers for 2 hours with intermittent exercise to exhaust with DEP mass concentration near 100 microg/m3. Exposures to nitrogen dioxide (NO2) near 0.35 ppm (similar to its concentration in DE) and to filtered air (FA) served as controls. Blood was drawn before exposure on day 1 and again the next morning (day 2). Sputum was induced only on day 2. Bronchial reactivity was measured -1 hour after exposure ended. Supplementary endpoints included measures of blood coagulation status, cardiopulmonary physiology, and symptoms. Each phase employed 15 subjects with asthma; 3 subjects participated in both phases. In Phase 1, airway reactivity was measured with inhaled methacholine; in Phase 2, with inhaled cat allergen. We found little biologic response to DE exposure compared with exposure to control atmospheres. In Phase 1, interleukin 4 (IL-4) in sputum showed an estimated 1.7-fold increase attributable to DE exposure, which was close to statistical significance; airway resistance increased modestly but significantly on day 2 after DE exposure; and nonspecific symptom scores increased significantly during DE exposure. In Phase 2, indicators of airway inflammation in sputum showed a possibly meaningful response: polymorphonuclear leukocytes (PMNs) and eosinophils increased after DE exposure, whereas macrophages decreased. IgE in sputum and the bronchoconstrictive response to cat allergen varied significantly between atmospheres, but not in patterns consistent with our primary hypothesis. Symptom score changes relatable to DE exposure were smaller than those in Phase 1 and not statistically significant. Controlled exposures, lasting 2 hours with intermittent exercise, to diluted DE at a particle mass concentration of 100 microg/m3 did not evoke clear and consistent lower-airway or systemic immunologic or inflammatory responses in mildly asthmatic subjects, with or without accompanying challenge with cat allergen. Likewise, these DE exposures did not significantly increase nonspecific or allergen-specific bronchial reactivity. A few isolated statistically significant or near-significant changes were observed during and after DE exposure, including increases in nonspecific symptoms (e.g., headache, nausea) suggestive of subtle, rapid-onset systemic effects. It is possible the lower respiratory tract is more resistant than the nose to adjuvant effects of diesel particles on allergic inflammation, so that no meaningful effects occur under exposure conditions like these. Alternatively, the experimental conditions may have been near a threshold for finding effects. That is, important lower respiratory effects may occur but may be detectable experimentally with slightly higher DEP concentrations, longer exposures, more invasive testing (e.g., bronchoalveolar lavage), or more susceptible subjects. However, ethical and practical barriers to such experiments are considerable.

Pulmonary vascular heterogeneity and the Starling hypothesis.

It has generally been assumed that movement of fluid between the pulmonary microvasculature and surrounding tissues is governed by a "Starling" balance of hydrostatic and protein osmotic forces similar to that which prevails in the extremities. However, both recent and older observations suggest that the lungs are more resistant to edema formation than most other organs. Several structural aspects of the lung may account for protection of the airspaces from edema formation. The pulmonary microvasculature, which comprises >70% of the pulmonary circulatory bed, appears to be less permeable to fluid and electrolytes than the endothelium of the pulmonary arteries and veins and other microvascular exchange areas. This arrangement may help explain why early edema is confined to the perivascular and peribronchial regions and why lymphatics do not reach the alveoli. Unlike the peripheral vasculature, which is compressed by edema formation, the extra-alveolar vessels remain tethered open by airway distention, even when interstitial pressures rise above those in the vessels. This may also facilitate return of proteins to the circulation. Ultrafiltration of plasma may lower local protein concentrations in the interstitium, thereby slowing further edema formation. Transendothelial reabsorption of fluid may also be altered by vesicular transport.

Indicator dilution measurements of extravascular lung water: basic assumptions and observations.

Since they were introduced more than five decades ago, a variety of single-pass indicator, thermal, and osmotic dilution approaches have been developed for detecting and measuring excess fluid in the lungs. This brief review discusses why studies of the extravascular lung water (EVLW) continue to intrigue physiologists and clinicians and the likelihood that they will become sufficiently reliable for more widespread use. Emphasis is placed on the basic assumptions that underlie these measurements and limitations imposed by the nature of the data that are collected. A distinction is made between approaches that are based on compartmental models of solute and water exchange and those that represent extensions of more conventional washout procedures, which have been utilized extensively for measurements of gas volumes in the lungs. Although the compartmental approach has been used to simplify indicator dilution studies by eliminating the need for a vascular indicator, it is based on assumptions that may not be realistic. Early recirculation inevitably limits the period in which observations can be made and impairs detection of those portions of the lungs with decreased perfusion. These general principles are also used to develop a new method of analyzing osmotic transient studies. A short account is given of EVLW observations that have been made in animals and humans. Both the sensitivity and specificity of EVLW measurements in humans are uncertain, and the normal clinical range of EVLW remains in doubt.

Asthma: new developments concerning immune mechanisms, diagnosis and treatment.

PURPOSE OF REVIEW: This brief review discusses how recent research may modify our understanding of the immunology of asthma. Consideration is given to the possible impact that these observations may have upon diagnostic and therapeutic strategies. RECENT FINDINGS: New studies indicate that current conceptions regarding the balance between Th1 and Th2 systems may need modification. The relationship between infection and the development of asthma in children has proven to be much more complex than originally suggested by the 'hygiene hypothesis'. In addition, important genetic differences have been found in the response of asthmatic patients to therapeutic agents. SUMMARY: Greater insight into the mechanisms responsible for asthma and the introduction of new drugs will depend in part upon the development of reliable and simple methods for detecting airway inflammation. As the immunologic aspects of asthma are dissected, we can expect that many more potential targets for treatment will be discovered, but treatment may have to be individualized for genetic differences between different individuals.

The effects of volatile salivary acids and bases on exhaled breath condensate pH.

RATIONALE: Recent studies have reported acidification of exhaled breath condensate (EBC) in inflammatory lung diseases. This phenomenon, designated "acidopnea," has been attributed to airway inflammation. OBJECTIVES: To determine whether salivary acids and bases can influence EBC pH in chronic obstructive pulmonary disease (COPD). METHODS: Measurements were made of pH, electrolytes, and volatile bases and acids in saliva and EBC equilibrated with air in 10 healthy subjects and 10 patients. RESULTS: The average EBC pH in COPD was reduced (normal, 7.24 +/- 0.24 SEM; range, 6.11-8.34; COPD, 6.67 +/- 0.18; range, 5.74-7.64; p = 0.079). EBCs were well buffered by NH(4)(+)/NH(3) and CO(2)/HCO(3)(-) in all but four patients, who had NH(4)(+) concentrations under 60 micromol/L, and acetate concentrations that approached or exceeded those of NH(4)(+). Saliva contained high concentrations of acetate (approximately 6,000 micromol/L) and NH(4)(+) (approximately 12,000 micromol/L). EBC acetate increased and EBC NH(4)(+) decreased when salivary pH was low, consistent with a salivary source for these volatile constituents. Nonvolatile acids did not play a significant role in determining pH of condensates because of extreme dilution of respiratory droplets by water vapor (approximately 1:12,000). Transfer of both acetic acid and NH(3) from the saliva to the EBC was in the gas phase rather than droplets. CONCLUSIONS: EBC acidification in COPD can be affected by the balance of volatile salivary acids and bases, suggesting that EBC pH may not be a reliable marker of airway acidification. Salivary acidification may play an important role in acidopnea.

Epithelial lining fluid solute concentrations in chronic obstructive lung disease patients and normal subjects.

The exhaled breath condensate (EBC) method represents a new, noninvasive way to detect inflammatory and metabolic markers in the fluid that covers the airways [epithelial lining fluid (ELF)]. However, respiratory droplets represent only a very small and variable fraction of the EBC, most (approximately 99.99%) of which is water vapor. Our objective was to show that ELF concentrations could be calculated from EBC values by using any of three dilutional indicators (urea, total cations, and conductivity) in nine normal and nine chronic obstructive lung disease (COPD) subjects. EBC concentrations of Na(+), K(+), Ca(2+), Mg(2+), total cations, urea, and conductivity varied over a 10-fold range among individuals, but concentrations of these constituents (except Ca(2+)) remained well correlated (r(2) = 0.44-0.83, P < 0.001). Dilution (D) of respiratory droplets in water vapor was calculated by dividing plasma concentrations of the dilutional indicators by EBC concentrations. Estimates of D were not significantly different among these indicators, and urea D averaged 10,800 +/- 2,100 (SE) in normal and 12,600 +/- 3,300 in COPD subjects. Although calculated Na(+) concentrations in the ELF were less than one-half those in plasma, and concentrations of K(+), Ca(2+), and Mg(2+) exceeded those in plasma, total cation concentrations in ELF were not significantly different from those in plasma, indicating that ELF is isotonic in both normal and COPD subjects. EBC amylase concentrations (measured with an ultrasensitive procedure) indicated that saliva represented <10% of the respiratory (ELF) droplets in all but three samples. Dilutional and salivary markers are essential for interpretation of EBC studies.