The immunopathogenesis of chronic obstructive pulmonary disease: insights from recent research

Chronic obstructive pulmonary disease (COPD) progression is characterized by accumulation of inflammatory mucous exudates in the lumens of small airways, and thickening of their walls, which become infiltrated by innate and adaptive inflammatory immune cells. Infiltration of the airways by polymorphonuclear and mononuclear phagocytes and CD4 T cells increases with COPD stage, but the cumulative volume of the infiltrate does not change. By contrast, B cells and CD8 T cells increase in both the extent of their distribution and in accumulated volume, with organization into lymphoid follicles. This chronic lung inflammation is also associated with a tissue repair and remodeling process that determines the ultimate pathologic phenotype of COPD. Why these pathologic abnormalities progress in susceptible individuals, even after removal of the original noxious stimuli, remains mysterious. However, important clues are emerging from analysis of pathologic samples from patients with COPD and from recent discoveries in basic immunology. We consider the following relevant information: normal limitations on the innate immune system's ability to generate adaptive pulmonary immune responses and how they might be overcome by tobacco smoke exposure; the possible contribution of autoimmunity to COPD pathogenesis; and the potential roles of ongoing lymphocyte recruitment versus in situ proliferation, of persistently activated resident lung T cells, and of the newly described T helper 17 (Th17) phenotype. We propose that the severity and course of acute exacerbations of COPD reflects the success of the adaptive immune response in appropriately modulating the innate response to pathogen-related molecular patterns ("the Goldilocks hypothesis").     

New insights into the immunology of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a heterogeneous syndrome associated with abnormal inflammatory immune responses of the lung to noxious particles and gases. Cigarette smoke activates innate immune cells such as epithelial cells and macrophages by triggering pattern recognition receptors, either directly or indirectly via the release of damage-associated molecular patterns from stressed or dying cells. Activated dendritic cells induce adaptive immune responses encompassing T helper (Th1 and Th17) CD4+ T cells, CD8+ cytotoxicity, and B-cell responses, which lead to the development of lymphoid follicles on chronic inflammation. Viral and bacterial infections not only cause acute exacerbations of COPD, but also amplify and perpetuate chronic inflammation in stable COPD via pathogen-associated molecular patterns. We discuss the role of autoimmunity (autoantibodies), remodelling, extracellular matrix-derived fragments, impaired innate lung defences, oxidative stress, hypoxia, and dysregulation of microRNAs in the persistence of the pulmonary inflammation despite smoking cessation.     

New insights into the pathophysiology of mild chronic obstructive pulmonary disease

The classification of mild chronic obstructive pulmonary disease (COPD) requires a postbronchodilator forced expiratory volume in 1 s (FEV₁) to forced vital capacity ratio <0.7 and an FEV₁ ≥80% predicted. Given their relatively well-preserved spirometry, some have argued that respiratory symptoms in patients with mild COPD are unlikely to be related to pulmonary function abnormalities and that early detection of COPD is a ‘waste of resources’. Despite this viewpoint, there is emerging clinical and physiological evidence of peripheral airway dysfunction, diminished quality of life and reduced physical activity levels, and increased mortality, hospitalizations, dyspnea and exercise intolerance in patients with mild COPD compared with healthy controls. The purpose of the present focused review was to summarize recent research regarding the pathophysiology and treatment of mild COPD.     

State of the art. Chronic obstructive pulmonary disease, inflammation, and lung cancer

Both lung cancer and chronic obstructive pulmonary disease (COPD) are associated with cigarette smoking, which, by generating reactive oxidant species, induces a chronic inflammatory state in the lung. Activation, particularly of nuclear factor-kappaB, occurs in both cancer and COPD, and expression of a number of genes is altered in both diseases. In lung cancer, DNA damage, lack of DNA repair, and genomic instability predominate, whereas matrix degradation, lack of repair, and an intense immune response predominate in COPD. The reasons for the different responses to a common inflammatory response induced by smoking remain to be determined, but likely lie in genetic polymorphisms in genes that regulate genome integrity in cancer and that regulate the immune response to tissue destruction in COPD.     

Survival after lung volume reduction in chronic obstructive pulmonary disease: insights from small airway pathology

RATIONALE: COPD is associated with reduced life expectancy. OBJECTIVES: To determine the association between small airway pathology and long-term survival after lung volume reduction in chronic obstructive pulmonary disease (COPD) and the effect of corticosteroids on this pathology. METHODS: Patients with severe (GOLD-3) and very severe (GOLD-4) COPD (n = 101) were studied after lung volume reduction surgery. Respiratory symptoms, quality of life, pulmonary function, exercise tolerance, chest radiology, and corticosteroid treatment status were assessed preoperatively. The severity of luminal occlusion, wall thickening, and the presence of small airways containing lymphoid follicles were determined in resected lung tissue. Kaplan-Meier survival analysis and Cox proportional hazards models were used to determine the relationship between survival and small airway pathology. The effect of corticosteroids on this pathology was assessed by comparing treated and untreated groups. MEASUREMENTS AND MAIN RESULTS: The quartile of subjects with the greatest luminal occlusion, adjusted for covariates, died earlier than subjects who had the least occlusion (hazard ratio, 3.28; 95% confidence interval, 1.55-6.92; P = 0.002). There was a trend toward a reduction in the number of airways containing lymphoid follicles (P = 0.051) in those receiving corticosteroids, with a statistically significant difference between the control and oral +/- inhaled corticosteroid-treated groups (P = 0.019). However, corticosteroid treatment had no effect on airway wall thickening or luminal occlusion. CONCLUSIONS: Occlusion of the small airways by inflammatory exudates containing mucus is associated with early death in patients with severe emphysema treated by lung volume reduction surgery. Corticosteroid treatment dampens the host immune response in these airways by reducing lymphoid follicles without changing wall thickening and luminal occlusion.     

Systemic inflammation and skeletal muscle dysfunction in chronic obstructive pulmonary disease: state of the art and novel insights in regulation of muscle plasticity

Systemic inflammation is a recognized hallmark of chronic obstructive pulmonary disease pathogenesis. Although the origin and mechanisms responsible for the persistent chronic inflammatory process remain to be elucidated, it is recognized that it plays an important role in skeletal muscle pathology as observed in chronic obstructive pulmonary disease and several other chronic inflammatory disorders. This article describes state-of-the-art knowledge and novel insights in the role of inflammatory processes on several aspects of inflammation-related skeletal muscle pathology and offers new insights in therapeutic perspectives.     

Epidemiology of chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a leading cause of world-wide mortality and disability. On average approximately 5-15% of adults in industrialized countries have COPD defined by spirometry. In 1990, COPD was considered to be at the twelfth position world-wide as a cause of combined mortality and disability but is expected to become the fifth cause by the year 2020. COPD has a chronic long-lasting course characterized by irreversible decline of forced expiratory volume in one second (FEV1), increasing presence of dyspnoea and other respiratory symptoms, and progressive deterioration of health status. After diagnosis the 10-yr survival rate is approximately 50% with more than one-third of patients dying due to respiratory insufficiency. Several environmental exposures such as air pollution increase the risk of death in COPD patients. The aetiology of COPD is overwhelmingly dominated by smoking although many other factors could play a role. Particular genetic variants are likely to increase the susceptibility to environmental factors although little is known about which are the relevant genes. There is clear evidence about the role of the alpha-1-antitrypsin but the fraction of COPD attributable to the relevant variants is only 1%. Phenotypic traits that are considered to play a role in the development of COPD include sex, with females being at a higher risk, bronchial responsiveness and atopy. There is strong causal evidence regarding the relationship between smoking and COPD with decline in FEVI levelling off after smoking cessation. Passive smoking has been found to be associated with a small though statistically significant decline in FEV1. Other risk factors that are likely to be relevant in the development of COPD are occupation, low socioeconomic status, diet and possibly some environmental exposures in early life. Although there is accumulating evidence that oxygen therapy, pharmacological treatment and rehabilitation may improve the course of chronic obstructive pulmonary disease, preventing smoking continues to be the most relevant measure, not only to prevent chronic obstructive pulmonary disease, but also to arrest its development.     

Exacerbations of chronic obstructive pulmonary disease.

Exacerbations of chronic obstructive pulmonary disease are of major importance in terms of their prolonged detrimental effects on patients, the acceleration in disease progression and high healthcare costs. There is still debate about how exacerbations should be defined and graded, and their mechanisms are poorly understood. The major causal agents are either bacteria or viral infections, or a combination of the two. Noninfective causes include air pollution and pulmonary embolus but, in some patients, no cause is identified. Exacerbations represent an increase in the inflammation that is present in the stable state, with increased numbers of inflammatory cells (particularly neutrophils), cytokines, chemokines and proteases in the airways, and increased concentrations of certain cytokines and C-reactive protein in the blood. There are presently no reliable biomarkers with which to predict exacerbations. Exacerbations have a long-lasting adverse influence on health status. High doses of bronchodilators are the mainstay of treatment and systemic corticosteroids have some benefit. The routine use of antibiotics remains controversial but they are of benefit with exacerbations of a bacterial origin. Noninvasive ventilation is beneficial in preventing the need for intubation and its important complications but it is not certain whether its use in stable patients prevents exacerbations. Although important advances have been made, more effective treatments are needed in the future for prevention and treatment of exacerbations.     

Transgenic and gene-targeted mice as models for chronic obstructive pulmonary disease.

Animal models play an important role in the understanding of the pathogenesis of chronic obstructive pulmonary disease (COPD). The applicability of findings to human COPD depends upon several factors, including the disease model, and similarities in mouse structure and function between species. There are many examples in the literature of transgenic mice that have contributed to the understanding of COPD. Several studies demonstrate the complexity of inflammatory networks and how unexpected findings in animal models have led to the search for new potential mediators in human disease. Gene-targeting studies into alpha(1)-antitrypsin (alpha(1)-AT) and emphysema in mice have demonstrated that the genetic locus for alpha(1)-AT in mice is very complex and that the loss of one gene is lethal in embryo lung development. This underlines the differences between mice and humans that limit the ability to translate between systems in some instances. Gene targeting has also highlighted complex roles for transforming growth factor-beta in COPD and has been used to determine important molecules and pathways in COPD. Both transgenic and gene-targeted models suffer limitations and their applicability to human chronic obstructive pulmonary disease may be dependant on several factors, some of which are still being learnt. The more that is known about similarities and differences, the better the knowledge will be that is gained to develop for chronic obstructive pulmonary disease.     

Thoracoabdominal motion in chronic obstructive pulmonary disease.

Studies of thoracoabdominal motion using the respiratory magnetometer were performed in 30 patients with chronic obstructive pulmonary disease. Volume equivalency of thoracic and abdominal deflections was established by using the concepts and methods developed by Konno and Mead. Twenty patients were ambulatory, although disabled, and 10 were in acute respiratory failure and were studied in a respiratory intensive care unit. Five of 20 ambulatory patients and 8 of 10 patients in acute respiratory failure showed inward abdominal motion coincident with outward rib cage motion during inspiration, suggesting ineffective diaphragmatic function. This pattern of thoracoabdominal motion was identical to that seen in 2 high quadriplegics with diaphragmatic paralysis when they were breathing entirely with their neck muscles. Inspiratory ascent of the diaphragm was confirmed fluoroscopically in 3 of the 5 ambulatory patients. Patients showing this pattern were generally severely disabled and had the largest residual volumes. Two abnormal patterns of thoracoabdominal motion were observed during the performance of maximal voluntary ventilation in the ambulatory patients. The first, seen in 9 of 20 patients, was characterized by reciprocal or paradoxical motion of rib cage and abdomen, with increase in rib cage volume associated with decrease in abdominal volume during inspiration. The second pattern, seen in 5 of 20 patients, showed complete disorganization of rib cage and abdominal motion, with no consistent or reproducible pattern. Thus, a significant proportion of patients with disabling chronic obstructive pulmonary disease show abnormalities in thoracoabdominal motion that are observable with the respiratory magnetometer and ofter by simple inspection. Most of these abnormalities suggest malfunction of respiratory muscles, particularly the diaphragm.     

Prognosis in severe chronic obstructive pulmonary disease.

A long-term prognostic study of 129 patients with severe chronic obstructive pulmonary disease (initial value for forced expiratory volume in 1 sec [FEV1] smaller than or equal to 1,000 ml) is reported. Data from the patients (72 per patient) were obtained in a clinically stable phase during the first hospital admission and subsequent regular outpatient visits; the data were processed using multiple regression and discriminant analysis. Five- and 10-year cumulative survival rates were 69 and 40 per cent, respectively. Prediction of survival rate was determined mainly by the rate of decrease in initial FEV1 per year and the degree of increase of initial FEV1 after administration of thiazinamium, a bronchodilator. Initial FEV1 values per se contributed to prediction only when they were less than 450 ml. Study of the data from the individual patients showed the presence of different types of decrease in FEV1: linear, exponential, combined linear-exponential, and phasic. FEV1 sometimes remained unchanged for several years or even showed an increase. No sudden decreases were observed. The better survival rate in patients with greater reversibility of airway obstruction after administration of thiazinamium has important bearing on treatment policy. The hypothesis is put forward that the better survival rate in the present study might be the result of continuing medical care. Comprehensive treatment, provided it includes a component directed at preventing and treating reversible airway obstruction, may be of major importance in determining survival in patients with severe chronic obstructive pulmonary disease. The value of so-called dominant, survival-predicting factors is considered to be of secondary importance; their main function is to alert the physician to the fact that prognosis as concerns survival may be unfavorable and that preventive and therapeutic measures should be taken without delay.     

Pulmonary hypertension in chronic obstructive pulmonary disease.

Pulmonary hypertension is a common complication of chronic obstructive pulmonary disease (COPD). Its presence is associated with shorter survival and worse clinical evolution. In COPD, pulmonary hypertension tends to be of moderate severity and progresses slowly. However, transitory increases of pulmonary artery pressure may occur during exacerbations, exercise and sleep. Right ventricular function is only mildly impaired with preservation of the cardiac output. Structural and functional changes of pulmonary circulation are apparent at the initial stages of COPD. Recent investigations have shown endothelial dysfunction and changes in the expression of endothelium-derived mediators that regulate vascular tone and cell growth in the pulmonary arteries of patients with mild disease. Some of these changes are also present in smokers with normal lung function. Accordingly, it has been postulated that the initial event in the natural history of pulmonary hypertension in COPD could be the lesion of pulmonary endothelium by cigarette-smoke products. Long-term oxygen administration is the only treatment that slows down the progression of pulmonary hypertension in chronic obstructive pulmonary disease. Nevertheless, with this treatment pulmonary artery pressure rarely returns to normal values and the structural abnormalities of pulmonary vessels remain unaltered. Vasodilators are not recommended on the basis of their minimal clinical efficacy and because they impair pulmonary gas exchange. Recognition of the role of endothelial dysfunction in the physiopathology of pulmonary hypertension in chronic obstructive pulmonary disease opens new perspectives for the treatment of this complication.     

Cardiac disease in chronic obstructive pulmonary disease

The cardiac manifestations of chronic obstructive pulmonary disease (COPD) are numerous. Impairments of right ventricular dysfunction and pulmonary vascular disease are well known to complicate the clinical course of COPD and correlate inversely with survival. The pathogenesis of pulmonary vascular disease in COPD is likely multifactorial and related to alterations in gas exchange and vascular biology, as well as structural changes of the pulmonary vasculature and mechanical factors. Several modalities currently exist for the assessment of pulmonary vascular disease in COPD, but right heart catheterization remains the gold standard. Although no specific therapy other than oxygen has been generally accepted for the treatment of pulmonary hypertension in this population, there has been renewed interest in specific pulmonary vasodilators. The coexistence of COPD and coronary artery disease occurs frequently. This association is likely related to shared risk factors as well as similar pathogenic mechanisms, such as systemic inflammation. Management strategies for the care of patients with COPD and coronary artery disease are similar to those without COPD, but care must be given to address their respiratory limitations. Arrhythmias occur frequently in patients with COPD, but are rarely fatal and can generally be treated medically. Use of beta-blockers in the management of cardiac disease, while a theoretical concern in patients with increased airway resistance, is generally safe with the use of cardioselective agents.