Neutrophils are recognized as major cellular mediators of inflammation. They contain specific and highly regulated mechanisms for controlling the expression of adhesion molecules that allow for their tethering and migration into inflammatory sites. These adhesion molecules not only are activated by exogenous pollutants but are regulated by endothelial and epithelial cell signals. Lipid mediators, such as platelet-activating factor, reactive oxygen and nitrogen species, and cytokines from airway epithelial cells, further control neutrophil functions such as infiltration and activation resulting in an increase in respiratory burst activity and release of granule enzymes, such as elastase. Furthermore, virus and bacteria products affect inflammation by increasing secondary epithelial mediators. However, once the endogenous or exogenous agents are expelled, neutrophil populations are programmed to die and are cleared by macrophage phagocytosis.

Some patients with COPD are prone to frequent exacerbations, which are an important determinant of health status. Such patients have elevated airway cytokine levels, suggesting the presence of increased inflammation that may increase their susceptibility to exacerbation. The inflammatory response during a COPD exacerbation is variable, but increases in interleukin-6 levels during the exacerbation are related to the presence of a common cold. Rhinovirus infection is the most important etiologic factor in COPD exacerbations and is an important target for preventive therapy. The reduction of COPD exacerbations will have an important impact on the considerable morbidity and mortality associated with COPD.

This article explores the hypothesis that dyspnea in patients with COPD arises from an imbalance between the load placed on the respiratory muscle pump and its capacity. Evidence to support this concept is presented, and possible therapeutic approaches are discussed.

The pathogenesis and clinical manifestations of COPD are not restricted to pulmonary inflammation and structural remodeling. Rather, this disorder is associated with clinically significant systemic alterations in biochemistry and organ function. The systemic aspects of COPD include oxidative stress and altered circulating levels of inflammatory mediators and acute-phase proteins. Indeed, an impaired endogenous oxidant-antioxidant balance has been reported in patients experiencing exacerbations of COPD, and others have observed altered circulating levels of several cytokines and adhesion molecules in patients with stable disease. As in other chronic inflammatory conditions, weight loss, muscle wasting, and tissue depletion are commonly seen in COPD patients. Selective wasting of fat-free mass coupled with impaired respiratory and peripheral muscle function and a reduced capacity for exercise occur in COPD patients. Indeed, weight loss may directly impact poor prognosis in COPD patients. The mechanisms underlying weight loss and muscle wasting are incompletely understood but likely involve an imbalance in ongoing processes of protein degradation and replacement. This may include alterations in the relative levels or activities of endocrine hormones such as insulin, growth hormone, testosterone, and glucocorticoids. Furthermore, chronic systemic inflammation involving cytokines such as interleukin-1 and tumor necrosis factor-alpha may be associated with these hormonal changes and muscle wasting in COPD patients. This review includes a discussion of the mechanisms of skeletal muscle fiber protein metabolism/catabolism, the potential roles of endogenous cytokines in protein loss, and the possibility that novel drugs that inhibit cytokine signaling may provide benefits by reducing muscle wasting and cachexia, thereby improving the prognosis and quality of life among COPD patients.

COPD continues to cause a heavy health and economic burden both in the United States and around the world. Some of the risk factors for COPD are well-known and include smoking, occupational exposures, air pollution, airway hyperresponsiveness, asthma, and certain genetic variations, although many questions, such as why < 20% of smokers develop significant airway obstruction, remain. Precise definitions of COPD vary and are frequently dependent on an accurate diagnosis of the problem by a physician. These differences in the definition of COPD can have large effects on the estimates of COPD in the population. Furthermore, evidence that COPD represents several different disease processes with potentially different interventions continues to emerge. In most of the world, COPD prevalence and mortality are still increasing and likely will continue to rise in response to increases in smoking, particularly by women and adolescents. Resources aimed at smoking cessation and prevention, COPD education and early detection, and better treatment will be of the most benefit in our continuing efforts against this important cause of morbidity and mortality.

In the last 200 years or so, the recognition, diagnosis, and understanding of the pathogenesis of COPD have evolved considerably. Over the past few decades, various definitions of COPD and its "components" also have developed. Despite this, however, the treatment options for patients with this relentlessly progressive disorder are relatively limited. In the mid-19th century, the introduction of the spirometer yielded a powerful tool for the diagnosis of COPD. The currently available small, cheap spirometers hold great promise to help patients and their physicians closely monitor lung function. Early recognition of the close associations among emphysema and, more recently, small airways disease, and impaired airflow is discussed. This review also stresses the importance of the identification of COPD in its initial stages and the early onset of appropriate treatment. The therapy for COPD has changed in the last 40 years. Drug therapies in the 1960s included potassium iodide and ephedrine. Corticosteroids were not used, and oxygen therapy and exercise were actually contraindicated. Modern therapy for COPD is now more systematic and includes the use of bronchodilators and corticosteroids to improve airflow, in addition to oxygen therapy, pulmonary rehabilitation and, in selected patients, lung volume reduction surgery. The causal link between the chronic inhalation of tobacco smoke and COPD is beyond doubt, and smoking cessation remains the most important goal for patients. It is hoped that new, more effective therapies will soon be available for the treatment of this disabling disorder to provide improvement in symptoms and patient quality of life and to reduce or stop the rate of disease progression and mortality in patients with COPD.

The purpose of this article is to familiarize chest physicians with recent advances in airway imaging, with an emphasis on the emerging role of two-dimensional reformatted and three-dimensional CT reconstructed images in the assessment of central airway disorders.

In the United States, in both sexes and all races, long-term heavy alcohol consumption (of any beverage type) is the leading cause of a nonischemic, dilated cardiomyopathy, herein referred to as alcoholic cardiomyopathy (ACM). ACM is a specific heart muscle disease of a known cause that occurs in two stages: an asymptomatic stage and a symptomatic stage. In general, alcoholic patients consuming > 90 g of alcohol a day (approximately seven to eight standard drinks per day) for > 5 years are at risk for the development of asymptomatic ACM. Those who continue to drink may become symptomatic and develop signs and symptoms of heart failure. ACM is characterized by an increase in myocardial mass, dilation of the ventricles, and wall thinning. Changes in ventricular function may depend on the stage, in that asymptomatic ACM is associated with diastolic dysfunction, whereas systolic dysfunction is a common finding in symptomatic ACM patients. The pathophysiology of ACM is complex and may involve cell death (possibly due to apoptosis) and changes in many aspects of myocyte function. ACM remains an important cause of a dilated cardiomyopathy, and in latter stages can lead to heart failure. Alcohol abstinence, as well as the use of specific heart failure pharmacotherapies, is critical in improving ventricular function and outcomes in these patients.

Our current understanding of the pathogenesis of sepsis suggests that bacteria as well as bacterial-derived products activate an uncontrolled network of host-derived mediators such as proinflammatory cytokines (ie, tumor necrosis factor [TNF] and interleukin [IL]-1beta), which can ultimately lead to cardiovascular collapse and death. Despite the potentially important role that TNF and IL-1beta may play in producing cardiac dysfunction in human septic shock, little is known with regard to the basic biochemical mechanism(s) by which bacterial pathogens induce their expression in the heart. A major advance in understanding the early events that are downstream from bacterial-mediated signaling has been the identification of Toll-like receptors (TLRs). TLR-mediated signaling is known to activate the transcription factor nuclear factor-kappaB and to upregulate TNF expression. It has recently been shown that the heart expresses TLRs, raising the possibility that these receptors may be responsible for mediating the deleterious effects of bacterial pathogens on cardiac function. In this review, we will discuss the emerging role for TLRs in the pathogenesis of the cardiovascular collapse that occurs during sepsis.

The prevalence of allergic respiratory diseases, asthma and allergic rhinoconjunctivitis, has increased since the advent of industrialization. The inverse relationship between the number of infections early in life and atopy has been interpreted as the "hygiene hypothesis." That is, many infections early in life promote the development of T helper type 1 cytokines, while fewer infections early in life favor the development of T helper type 2 (Th2) cytokines and atopy. An alternate interpretation of the same data, that atopy is protective against infections early in life, is rarely considered. With epidemiologic, historical, and immunologic data, I suggest that human evolution has favored individuals with an atopic predisposition. Th2 immune responses promote parity, and ensure successful pregnancy and term birth; provide the infant protection against infections and the inflammation induced by common pathogens in the first years of life until the immune system matures; and protect young adults exposed to viral respiratory pathogens. These traits are of particular value with the advent of industrialization, especially so in the era prior to the development of antibiotics. This theory contradicts the assumption that there is no biological or evolutionary advantage for allergic disease to exist in humans and has significant implications for our current and future treatments of allergic diseases.

There are a number of difficulties in the conduct of randomized trials in the critically ill. These include difficulties in the definition of diseases and syndromes, a heterogenous population of patients undergoing a variety of therapeutic interventions, and outcomes that may not be able to discriminate between beneficial and risky therapies. Following a brief description of different randomized clinical trials (RCTs) and design philosophies, we outline the effects of different design choices in the complex critical care environment. Once the study topic has been determined to be relevant and important, then the potential investigator must establish whether efficacy or effectiveness will be the focus of the RCT. If an effectiveness design philosophy is chosen, then broad representation of study sites, liberal eligibility criteria, easily implemented intervention study protocols, and patient-centered outcomes should be chosen. The potential investigator wishing to establish efficacy will conduct the study in the centers of excellence and adopt stringent eligibility criteria, rigorous study protocols, and opt for outcomes that will be sensitive to change. In conclusion, we describe some of the major challenges and possible solutions to help a potential investigator through the myriad of difficulties in initiating an RCT in a complex environment.

A number of studies have shown a high incidence of lung cancer in patients with idiopathic pulmonary fibrosis (9.8 to 38%) compared to control subjects (2 to 6.4%). A similar trend occurs in other entities that affect the interstitial lung compartment, such as systemic sclerosis and sarcoidosis, as well as occupational diseases. The pathogenesis of lung cancer in patients with diffuse pulmonary fibrosis is still unclear. Recent progress in molecular and cellular biology has shed some light on the possible interactions of several types of inflammatory cells, following the deleterious effects of toxic factors leading to alveolitis, and destruction and disorganization of lung parenchyma, which results in fibrosis. Further research in the field would enhance our understanding of the pathogenic mechanisms of cancer development in these patients, and to explain the reason for the different incidence of lung cancer in patients with various interstitial lung diseases.

Postoperative lung injury is one of the most frequent complications of cardiac surgery that impacts significantly on health-care expenditures and largely has been believed to result from the use of cardiopulmonary bypass (CPB). However, recent comparative studies between conventional and off-pump coronary artery bypass grafting have indicated that CPB itself may not be the major contributor to the development of postoperative pulmonary dysfunction. In our study, we review the associated physiologic, biochemical, and histologic changes, with particular reference to the current understanding of underlying mechanisms. Intraoperative modifications aiming at limiting lung injury are discussed. The potential benefits of maintaining ventilation and pulmonary artery perfusion during CPB warrant further investigation.

The incidence of supraventricular arrhythmias remains high following open-heart surgery. The most common of these arrhythmias are atrial fibrillation and flutter (AFF), for which treatment is not well defined. Recent studies have focused on prophylactically treating patients in an attempt to reduce postoperative AFF. Several studies have shown that sotalol and amiodarone are both effective in reducing AFF following heart surgery. However, no studies have been done comparing both drugs.

Asthma is the most common chronic childhood disease in developed nations and is a complex disease that has high social and economic costs. Asthma and its associated intermediate phenotypes are under a substantial degree of genetic control. Identifying the genes underlying asthma offers a means of better understanding its pathogenesis, with the promise of improving preventive strategies, diagnostic tools, and therapies. A number of chromosomal regions containing genes influencing asthma and atopy have been identified consistently by different groups, and a role for several candidate genes has been established.

Traditionally, corticosteroids have been administered to patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) to ward off detrimental physiologic alterations associated with activation of the systemic inflammatory response, yet few well-controlled investigations exist, and use of these drugs in this setting remains controversial. This review article critically examines the results of clinical investigations in this area, and certain conclusions are suggested. The constellation of findings indicate that corticosteroids offer no clinical benefits to patients undergoing cardiac surgery with CPB and in fact may be detrimental. Further directions for clinical research in this area are also suggested.

Genetic variants of key hemostatic mediators increasingly have been proposed as risk factors for atherothrombosis. The Hormone and Estrogen/Progestin Replacement Study group recently reported that the initiation of estrogen replacement in postmenopausal women with known coronary heart disease is associated with an early increase in cardiovascular events. A putative genetic susceptibility factor has been proposed a potential mediator of this increased event risk. This review outlines the recent literature to support the premise for this important proposal. Genetic profiling has great potential to improve the safety and efficacy of individualized pharmacotherapy in postmenopausal women and other at-risk populations for the prevention of cardiovascular disease.

Major pulmonary embolism (PE) results whenever the combination of embolism size and underlying cardiopulmonary status interact to produce hemodynamic instability. Physical findings and standard data crudely estimate the severity of the embolic event in patients without prior cardiopulmonary disease (CPD) but are unreliable indicators in patients with prior CPD. In either case, the presence of shock defines a threefold to sevenfold increase in mortality, with a majority of deaths occurring within 1 h of presentation. A rapid integration of historical information and physical findings with readily available laboratory data and a structured physiologic approach to diagnosis and resuscitation are necessary for optimal therapeutics in this "golden hour." Echocardiography is ideal because it is transportable, and is capable of differentiating shock states and recognizing the characteristic features of PE. Spiral CT scanning is evolving to replace angiography as a confirmatory study in this population. Thrombolytic therapy is acknowledged as the treatment of choice, with embolectomy reserved for those in whom thrombolysis is contraindicated.

We report two cases of septic pulmonary embolism associated with periodontitis. Chest CT revealed multiple nodular shadows with features characteristic of septic pulmonary embolism in both patients. Both patients had toothache, fever, and chest pain, and showed findings of periodontitis at initial presentation. Antimicrobial agents combined with dental surgery were successful in treatment. While septic pulmonary embolism from the lesions of periodontitis appears to be rare, periodontitis remains important in the differential diagnosis of septic pulmonary embolism.

Osteoporosis, with resulting fractures, is a significant problem in patients with advanced COPD. The etiology for the bone loss is diverse but includes smoking, vitamin D deficiency, low body mass index, hypogonadism, sedentary lifestyle, and use of glucocorticoids. Effective strategies to prevent bone loss and/or to treat osteoporosis include calcium and vitamin D, hormone replacement when indicated, calcitonin, and bisphosphonate administration. However, many patients remain undiagnosed until their first fracture because of the lack of recognition of the disease. With an increased awareness by pulmonologists and the increased use of preventive strategies, the impact of osteoporosis on those patients with COPD should decrease.