Combined pulmonary fibrosis and emphysema syndrome: a radiologic perspective.

Chronic obstructive pulmonary disease (that includes emphysema) results in significant morbidity and mortality worldwide. Idiopathic pulmonary fibrosis (IPF) is also a chronic and progressive parenchymal lung disease with an average survival of less than 5 years after diagnosis. Combined pulmonary fibrosis and emphysema (CPFE) is an important but still underdiagnosed syndrome. Its diagnosis is based on the radiological findings at computed tomography which consists of emphysema of the upper lung zones and fibrosis of the lower lung zones. Since this syndrome has a very bad prognosis, even worse than isolated finding of emphysema or fibrosis alone, early recognition and rapid treatment are important. In this article we will review and elucidate the radiologic appearance of this syndrome and highlight its clinical importance.

Randomised controlled trial of transcutaneous electrical muscle stimulation of the lower extremities in patients with chronic obstructive pulmonary disease.

BACKGROUND: Although exercise training improves exercise tolerance in most patients with chronic obstructive pulmonary disease (COPD), some patients with severe disease may not be able to tolerate exercise training due to incapacitating breathlessness. Transcutaneous electrical muscle stimulation (TCEMS) has been shown to improve muscle strength, muscle mass, and performance in paraplegics, patients with knee ligament injury, and patients with peripheral vascular disease. We hypothesised that TCEMS of the lower extremities can improve muscle strength and exercise tolerance in patients with moderate to severe COPD. METHODS: A randomised controlled trial of TCEMS of the lower extremities was performed in 18 medically stable patients of mean (SD) age 60.0 (1.5) years with a mean forced expiratory volume in 1 second (FEV(1)) of 1.03 (0.10) l (38% predicted) and residual volume/total lung capacity (RV/TLC) of 59 (2)%. Stimulation of the lower extremities was performed three times a week, 20 minutes each session, for six continuous weeks. Quadriceps and hamstring muscle strength, exercise capacity, and peak oxygen uptake were measured at baseline and after 6 weeks of stimulation. RESULTS: TCEMS improved both the quadriceps strength (by 39.0 (20.4)% v 9.0 (8.1)%, p=0.046) and hamstring muscle strength (by 33.9 (13.0)% v 2.9 (4.7)%, p=0.038) in the treated (n=9) and sham treated (n=9) groups, respectively. The improvement in muscle strength carried over to better performance in the shuttle walk test in the treated group (36.1% v 1.6% in the treated and sham groups respectively, p=0.007, Mann-Whitney U test). There was no significant change in lung function, peak workload, or peak oxygen consumption in either group. Muscle stimulation was well tolerated by the patients with no dropouts and better than 95% compliance with the protocol. CONCLUSIONS: TCEMS of peripheral muscles can be a useful adjunct to the comprehensive pulmonary rehabilitation of patients with COPD.

Smoking and chronic obstructive pulmonary disease.

Smoking is overwhelmingly the major cause of chronic bronchitis and emphysema worldwide. Additional risk factors for developing COPD are presented, along with the variables that govern cigarette smoke deposition in the lung. Major paradigms for the pathogenesis of COPD, including the protease-antiprotease and oxidant-antioxidant theories are described, and evidence for impaired reparative mechanisms in the causation of emphysema is noted. A description of the natural history of declining lung function in smokers and in the susceptible subset of smokers that ultimately develop smoking-induced COPD is accompanied by a discussion of the effects of smoking cessation on preservation of lung health. The disordered ventilation and gas-exchange physiology in the cigarette smoke-damaged lung is explained on the basis of the observed morphological changes.

Exercise training in chronic obstructive pulmonary disease.

Exercise limitation is a common and disturbing manifestation of COPD. The exercise intolerance is often caused by multiple interrelated anatomic and physiologic disturbances. Importantly, exercise tolerance can be improved despite the presence of fixed structural abnormalities in the lung. Exercise training, undertaken alone or in the context of comprehensive PR, improves exercise endurance and, to a lesser degree, the maximal tolerated workload of patients with COPD. Pulmonary rehabilitation also improves dyspnea and QOL. Exercise training and PR should be considered for all patients lacking contraindications who experience exercise intolerance despite optimal medical therapy. Lower-extremity training should be included routinely in the exercise prescription. The choice of type and intensity of training should be based primarily on the patient's individual baseline functional status, symptoms, needs, and long-term goals. When tolerated, high-intensity (continuous or interval) training may lead to greater improvements in aerobic fitness than low-intensity training but is not absolutely necessary to achieve gains in exercise endurance. Upper-extremity training should be undertaken when possible. Ventilatory muscle training should be considered for patients who continue to experience exercise limitation and breathlessness despite medical therapy and general exercise reconditioning. Exercise tolerance may improve following exercise training because of gains in aerobic fitness or peripheral muscle strength; enhanced mechanical skill and efficiency of exercise; improvements in respiratory muscle function, breathing pattern, or lung hyperinflation; as well as reduction in anxiety, fear, and dyspnea associated with exercise. Gains made in exercise tolerance can last up to 2 years following a limited duration (6-12 week) rehabilitation program.

Eosinophil-fibroblast interactions. Granule major basic protein interacts with IL-1 and transforming growth factor-beta in the stimulation of lung fibroblast IL-6-type cytokine production.

To test the hypothesis that eosinophil major basic protein (MBP) is an important regulator of fibroblast effector function, we characterized the effects of MBP on human lung fibroblast production of the IL-6-type cytokines, IL-6, IL-11, and leukemia inhibitory factor. Unstimulated fibroblasts did not produce substantial quantities of these cytokines, while IL-1 and TGF-beta(1) stimulated these cytokines in a potent fashion. MBP at doses < or = 44 micrograms/ml did not stimulate IL-6-type cytokine production. It did, however, interact in a synergistic, dose- and time-dependent fashion with rIL-1-alpha and TGF-beta(1) to further increase IL-6-type cytokine elaboration. These MBP-induced increases in cytokine production were associated with proportionate alterations in mRNA accumulation. In contrast, eosinophil-derived neurotoxin did not regulate fibroblast cytokine production, and MBP did not augment fibroblast granulocyte-macrophage-CSF, or type I collagen production, or fibroblast proliferation in this culture system. The effects of MBP could not be attributed to cell cytotoxicity or contaminants in the MBP preparations. They were, however, at least partially charge mediated, since heparin abolished the effects of MBP on IL-1-stimulated cells, and the surrogate cationic molecule poly-L-arginine mimicked the stimulatory effects of MBP on fibroblast IL-6-type cytokine elaboration. These studies demonstrate that MBP interacts in a synergistic fashion with rIL-1-alpha or TGF-beta(1) to further augment fibroblast IL-6-type cytokine production. They also demonstrate that this stimulation is pretranslationally mediated and due, in part, to the cationic nature of the MBP molecule. MBP regulation of fibroblast cytokine production may play an important role in the pathogenesis of eosinophilic disorders of the airway or other organs.

Airway management in respiratory emergencies.

Securing the airway is an important first step in respiratory emergencies. In this article, general principles of airway management are reviewed. The techniques of tracheal intubation, including surgical routes of airway access, are discussed in reference to special circumstances that can arise in acute airway management.

Cytokine regulation of human lung fibroblast hyaluronan (hyaluronic acid) production. Evidence for cytokine-regulated hyaluronan (hyaluronic acid) degradation and human lung fibroblast-derived hyaluronidase.

We characterized the mechanisms by which recombinant (r) tumor necrosis factor (TNF), IFN-gamma, and IL-1, alone and in combination, regulate human lung fibroblast hyaluronic acid (HA) production. Each cytokine stimulated fibroblast HA production. The combination of rTNF and rIFN-gamma resulted in a synergistic increase in the production of high molecular weight HA. This was due to a synergistic increase in hyaluronate synthetase activity and a simultaneous decrease in HA degradation. In contrast, when rTNF and rIL-1 were combined, an additive increase in low molecular weight HA was noted. This was due to a synergistic increase in hyaluronate synthetase activity and a simultaneous increase in HA degradation. Human lung fibroblasts contained a hyaluronidase that, at pH 3.7, depolymerized high molecular weight HA to 10-40 kD end products of digestion. However, hyaluronidase activity did not correlate with fibroblast HA degradation. Instead, HA degradation correlated with fibroblast-HA binding, which was increased by rIL-1 plus rTNF and decreased by rIFN-gamma plus rTNF. Recombinant IL-1 and rTNF weakly stimulated and rIL-1 and rTNF in combination further augmented the levels of CD44 mRNA in lung fibroblasts. In contrast, rIFN-gamma did not significantly alter the levels of CD44 mRNA in unstimulated or rTNF stimulated cells. These studies demonstrate that rIL-1, rTNF, and rIFN-gamma have complex effects on biosynthesis and degradation which alter the quantity and molecular weight of the HA produced by lung fibroblasts. They also show that fibroblast HA degradation is mediated by a previously unrecognized lysosomal-type hyaluronidase whose function may be regulated by altering fibroblast-HA binding. Lastly, they suggest that the CD44 HA receptor may be involved in this process.

Human airway macrophages. A technique for their retrieval and a descriptive comparison with alveolar macrophages.

We developed a technique to isolate and lavage a segment of a large human airway in vivo. Airway lavage and BAL were performed without significant complications 18 times on 17 normal volunteers. The mean +/- SEM volume of instillate used on all subjects totaled 31.3 +/- 2.7 ml with 47.1 +/- 3.8% of the fluid recovered. A total of 1.5 +/- 0.3 x 10(6) cells were retrieved. Cell viability averaged 71.3 +/- 4.6%. The majority of the cells were macrophages, 27.9 +/- 2.7%, and neutrophils, 28.4 +/- 6.0%. A descriptive comparison of airway macrophages using transmission electron microscopy with those retrieved from paired bronchoalveolar lavage (BAL) samples revealed that airway macrophages possessed more vacuoles (p less than 0.0001), fewer long microvilli (p less than 0.0001), and more membrane undulations (p less than 0.0001). In contrast, macrophages from both lavage locations demonstrated similar staining characteristics when stained with a panel of monoclonal antibodies. During lavage, all subjects experienced mild dyspnea that was relieved when the lavage was completed. One of three subjects tested during the procedure revealed O2 desaturation that was prevented by the inhalation of O2. We conclude that viable macrophages can be retrieved safely from airways of normal subjects and that, compared with macrophages present in BAL, these cells bear both similarities and dissimilarities that may portend differing functional capabilities.

Dendritic cells from rat lung are potent accessory cells.

Accessory cells are required for the induction of lymphocyte proliferation in response to mitogens or antigens. Rat pulmonary cells were tested for the presence of accessory activity in lymphocyte proliferation induced by sodium periodate. Buffer-perfused lungs were excised, minced, and enzymatically digested. The resulting pulmonary cells (PC) were separated into high density (HD-PC, 32 to 57%) and low density (LD-PC, 9 to 32%) fractions in a discontinuous density gradient of bovine plasma albumin (BPA). Both macrophages and dendritic cells were observed in the LD-PC by light microscopy. HD-PC, LD-PC, adherent LD-PC, nonadherent LD-PC, and a purified preparation of pulmonary dendritic cells (DC-P) were tested for accessory activity in the presence of periodate-treated, lymph-node-derived lymphocytes as responders. Most of the accessory activity was found in the LD-PC. Increasing numbers of LD-PC stimulated proliferation of responder lymphocytes in a linear, dose-dependent manner; higher numbers had a suppressive effect. Nonadherent LD-PC containing dendritic cells also produced a dose-dependent increase in periodate-induced lymphocyte proliferation, whereas adherent LD-PC, morphologically identified as macrophages, were suppressive. Removal of phagocytic macrophages from nonadherent LD-PC resulted in an eightfold increase in both the percent of DC-P present and the amount of accessory activity in the LD-PC. We conclude that pulmonary dendritic cells are potent accessory cells for periodate-induced lymphocyte proliferation.

A radioreceptor assay for propranolol and 4-hydroxypropranolol.

A radioreceptor assay for the measurement of propranolol and 4-hydroxypropranolol levels in plasma is described. Maximum sensitivity for propranolol was 1.2 +/- 0.15 ng/ml and for 4-hydroxypropranolol 4.2 +/- 0.4 ng/ml. Interassay and intra-assay variations for both were under 10%. Modifications in the radioreceptor assay permitted the measurements of total beta-adrenergic blocking activity and the separate contributions of parent drug and metabolite. When 4-hydroxypropranolol was stabilized, a composite level of total beta-adrenergic blocking activity in plasma was obtained. When the 4-hydroxy metabolite was oxidized, only the stable parent drug was detected. The difference in values between measurements made under these conditions was equivalent to the amount of 4-hydroxypropranolol in the sample. The radioreceptor assay was also used to measure the amount of free propranolol and 4-hydroxypropranolol. Under identical experimental conditions, more 4-hydroxypropranolol than propranolol circulated in the free form. These observations establish the feasibility of adapting the radioreceptor assay for propranolol to the measurement of total beta-adrenergic blocking activity and its components in plasma as well as to the measurement of free drug and metabolite levels.