Scope, background and definition of pulmonary rehabilitation.

The optimal therapy of an individual with chronic respiratory disease usually requires a combination of pharmacologic and non-pharmacologic therapies. A case of a 68-year-old man with advanced chronic obstructive pulmonary disease is given to illustrate this point. He is a recent ex-smoker with severe chronic obstructive pulmonary disease by spirometric criteria, frequent exacerbations of this disease, considerable recent health care utilization, dyspnea with minimal activities, severe functional status limitation, prominent systemic effects of the disease (e.g., weight loss) and substantial comorbidities. The primary respiratory disease cannot be isolated from and treated independently of these important factors. Pulmonary rehabilitation is an important therapeutic option in situations like this, providing a mode of integrating care, complementing otherwise standard medical therapy, and producing significant gains across multiple outcome areas of importance to the patient. Pulmonary rehabilitation has been defined by the American Thoracic Society and European Respiratory Society as: "an evidence-based, multidisciplinary, and comprehensive intervention for patients with chronic respiratory diseases who are symptomatic and often have decreased daily life activities. Integrated into the individualized treatment of the patient, pulmonary rehabilitation is designed to reduce symptoms, optimize functional status, increase participation, and reduce health care costs through stabilizing or reversing systemic manifestations of the disease". Its components include comprehensive assessment, education, exercise training, and psychosocial intervention. Outcomes assessment is usually performed for quality assessment. Pulmonary rehabilitation produces the greatest improvements of any available therapy in dyspnea, exercise capacity, and health-related quality of life. These gains are realized despite the fact that pulmonary rehabilitation has no direct effect on lung function. It works primarily through reducing the impact of the systemic manifestations of the disease and frequent comorbidity. Pulmonary rehabilitation also leads to substantial reductions in subsequent health care utilization, possibly through collaborative self-management strategies emphasized in the program. Although pulmonary rehabilitation has been utilized by astute clinicians for many years, its science has been developed over the past two decades.

Mechanisms and measures of exercise intolerance in chronic obstructive pulmonary disease.

The mechanisms for exercise intolerance in chronic obstructive pulmonary disease are complex and multifaceted. Although ventilatory limitation caused by abnormal pulmonary function is a major contributor to this phenomenon, other factors may play an important role in limiting exercise. These other factors include depressed cardiac function, respiratory and peripheral muscle weakness, nutritional imbalances, and psychologic factors. The assessment of the pulmonary patient who complains of decreased functional status must include examination and consideration of all these variables. Only by addressing and treating the combination of these variables as they present in an individual patient will clinicians have the potential to impact that individual's functional status and quality of life.

Amifostine modulation of bleomycin-induced lung injury in rodents.

Bleomycin is an effective anticancer agent whose treatment is limited by severe and potentially fatal pulmonary toxicity. This toxicity, characterized by alveolar inflammation and proliferative fibrosis, is mediated by active oxygen species and may result in disruption of the balance between type 2 pneumocyte apoptosis and fibroblast proliferation. The chemoprotectant activity of amifostine (Ethyol; Alza Pharmaceuticals, Palo Alto, CA/US Bioscience, West Conshohocken, PA) is attributed, in part, to the scavenging of active oxygen species. Therefore, it was of interest to study the effects of amifostine on ameliorating the pulmonary toxicities associated with bleomycin in animals. Studies in hamsters and mice demonstrate that pretreatment with amifostine reduces the pulmonary toxicity induced by bleomycin administration. The results of these preclinical studies suggest that amifostine may be clinically beneficial in reducing the severe pulmonary toxicity associated with bleomycin.

Modulation of bleomycin-induced pulmonary toxicity in the hamster by the antioxidant amifostine.

BACKGROUND: Bleomycin produces lung fibrosis in a wide variety of species. In humans, it can cause significant morbidity and mortality when used to treat malignancies such as lymphoma and testicular carcinoma. In rodents, it has been extensively used to study key mechanisms of lung injury and repair. Bleomycin pulmonary toxicity is mediated, at least in part, by the generation of active oxygen species. Amifostine, an aminothiol compound, is a cytoprotectant that is used with many antitumor agents and can act as a potent scavenger of free radicals. The authors hypothesized that amifostine could ameliorate bleomycin lung injury. METHODS: Hamsters weighing 120 g were given an intraperitoneal (IP) injection of amifostine (200 mg/kg, 1180 mg/m2) or saline with intratracheal (IT) bleomycin (1 unit) or saline, followed by daily IP amifostine or saline for 6 days. Lungs were assessed on Day 2 for acute lung injury, which was determined by wet-to-dry lung weight ratios. On Day 21, histologic assessment of fibrosis and biochemical analysis of lung hydroxyproline content were performed. RESULTS: No significant differences in morbidity or mortality were observed among the groups. Animals who received IT bleomycin, when compared with controls, had increased lung water measurements on Day 2 that were consistent with acute inflammation; on Day 21, they had pulmonary fibrosis, as measured by morphometric analysis, as well as increased hydroxyproline content. For animals treated with amifostine and bleomycin, significant decreases in wet-to-dry lung weight ratios were observed (mean +/- standard deviation, 4.5+/-1.2 vs. 10.2+/-2.7), as well as significant decreases in the percentage of fibrosis per lung (15.03%+/-3.27 vs. 37.26%+/-5.76) and hydroxyproline content (1.132+/-0.30 vs. 1.831+/-0.243). CONCLUSIONS: Amifostine significantly decreased the amount of acute lung injury and subsequent fibrosis in the hamster model of bleomycin-induced lung injury.

The epidermal growth factor receptor network in type 2 pneumocytes exposed to hyperoxia in vitro.

Hyperoxia is a well-characterized model of injury and repair of the lung. Type 1 cell damage is followed by type 2 cell proliferation and differentiation which restore normal structure and function. The epidermal growth factor receptor (EGFR) network is known to be a potent modulator of epithelial cell growth. Here we examine the EGFR network on isolated rat type 2 cells and SV40T-T2, a type 2 cell line, under normoxic conditions, after 24 and 48 h of in vitro hyperoxia, and after 24 h of normoxic recovery. EGF induces tyrosine phosphorylation of EGFRs in type 2 cells and SV40T-T2 cells, which decreases with hyperoxia and increases above normoxic levels in recovering cells, suggesting biphasic changes in receptor number or function with injury. The EGFR appears to be stimulated in an autocrine fashion in these cells. There is decreased DNA synthesis and proliferation in SV40T-T2 and isolated type 2 cells treated with tyrphostin B56, a specific EGFR inhibitor. Pretreatment with suramin, which binds to growth factor, results in increased EGFR tyrosine phosphorylation after stimulation, suggesting disruption of normal autocrine receptor downregulation. We have also identified transforming growth factor-alpha (TGF-alpha) in conditioned media (CM) from normoxic and hyperoxic SV40T-T2 and type 2 cells. Finally, we show increased EGF bioactivity in both bronchoalveolar lavage (BAL) from hyperoxic rats and CM from hyperoxic cells compared with normoxic controls. These findings support an integral role for an autocrine EGFR network in the type 2 cell response to injury.

gamma-Glutamyl transpeptidase is a polarized alveolar epithelial membrane protein.

In many diseases the lung is injured by oxidants. gamma-Glutamyl transpeptidase (GGT) is an ectoenzyme on the apical plasma membrane of many epithelial cells that protects against oxidants by replenishing intracellular glutathione. We sought to localize GGT within rat lungs in vivo and in cultured alveolar epithelial cells. In the adult rat lung, indirect immunofluorescence (IF) with a polyclonal antibody to triton-solubilized GGT revealed linear staining outlining the alveoli. Immunoelectron microscopy (IEM) localized the protein on the apical surface of the alveolar epithelial cells, but more densely on type I cells than type II cells, as well as on the apical surface of some ciliated bronchial cells. On Western blots of whole lung and isolated type II cell membrane proteins, the antibody predominantly recognized a broad protein band of 110-120 kDa, consistent with the uncleaved, glycosylated form of GGT. Over time in culture, isolated rat type II cells had increasing immunoreactivity on Western blots and indirect IF but decreasing enzyme activity. At 2 days in culture, confocal laser scanning microscopy demonstrated that GGT was polarized to the apical surface of nonconfluent type II cells. Thus GGT is a polarized apical membrane protein in type I and II cells, suggesting a role in the metabolic functions of these cells. The increased immunoreactive GGT of cultured type II cells is consistent with their acquisition of properties similar to type I cells, but the lack of correlation between immunoreactive protein and enzyme activity awaits explanation.

Upregulation of rat lung Na-K-ATPase during hyperoxic injury.

A major function of the alveolar epithelium is to keep the airspace free of fluid and preserve gas exchange. Since Na-K-ATPase is believed to be important in this process, we hypothesized that Na-K-ATPase in the rat lung would increase in response to acute lung injury with pulmonary edema. Na-K-ATPase localization, mRNA expression, and protein levels were determined in hyperoxic lung injury. Adult male rats were exposed to greater than 97% oxygen for 60 h followed by recovery in room air. At 60 h of hyperoxia, the wet-to-dry lung weights increased, consistent with edema. Within the alveolar capillary region, the sodium pump remained localized to the type II cell basolateral membrane by immunocytochemistry. By Northern blot analysis, the level of total lung mRNA expression of the alpha 1- and beta-subunits of Na-K-ATPase increased three- to fourfold during hyperoxia compared with unexposed rats. Total lung Na-K-ATPase membrane protein, visualized with a Western blot technique, appeared to increase by 24 h of hyperoxic insult when compared with levels in unexposed animals. The increase in sodium pump gene expression that occurs during hyperoxic insult, followed by an increase in sodium pump membrane protein, suggests that type II cells increase their Na-K-ATPase synthesis as an early response to pulmonary edema and/or hyperoxia.