Current Respiratory Medicine Reviews - Volume 1, Issue 3, 2005

Breathing movements are directed both reflexly by neurons in the medulla and pons and behaviorally through cortical and limbic neurons. The two modes of control have afferent and efferent interconnections and interact continuously but their relative influences shift considerably through the sleep-waking cycle. In an awaked state behavioral control prevents apnea and by itself is able to maintain normal blood gas tensions except during exercise above the anerobic threshold. During sleep the maintenance of breathing depends on input from chemoreceptors. If apnea should occur during sleep, this is regularly followed by arousal so as to return the control of breathing to the behavioral system. In certain pathological states breathing is persistently regulated either automatically as in the "locked in" syndrome or voluntarily in the congenital central hypoventilation syndrome. Respiratory movements and forces produce sensations that can be accurately perceived and when sufficiently intense result in symptoms of shortness of breath or dyspnea. This in turn can initiate volitional adjustments in the level and pattern of breathing. Dyspnea can have both beneficial and adverse effects. In asthmatics, dyspnea serves as an early warning signal of airway narrowing; but in patients with chronic airways obstruction or in patients with normal lungs and panic disorder dyspnea may be an incapacitating symptom. Recent investigations using techniques such as functional brain imaging and electrical and magnetic brain stimulation as well as increasingly sophisticated psychophysical approaches have provided important insights into the workings of the suprapontine regulation of breathing and its role in health and disease.

Pulmonary embolism is a common medical problem and although many patients have a benign clinical course there is still appreciable morbidity and mortality associated with the diagnosis. It is generally accepted that thrombolysis is the treatment of choice in patients with haemodynamic compromise but the management of haemodynamically stable patients with large pulmonary embolism is less well defined. A significant proportion of this latter group have a complicated hospital course and require escalation of therapy. There is increasing interest in markers that can potentially identify at risk patients who would benefit from intensive monitoring and therapy. Conversely these markers would also identify low risk patients who could be managed on an outpatient basis alone. This article reviews the current evidence for the use of the clinical history and examination, electrocardiogram, echocardiography, computed tomography and cardiac biochemical markers, principally troponin and brain natriuretic peptide, for risk stratification in pulmonary embolism.

The multifunctional cytokine, tumor necrosis factor-alpha (TNF-α), is released from host cells in response to diverse injurious stimuli and is elevated during acute lung injury. Increased levels of TNF-α are found in both the bloodstream and bronchoalveolar lavage fluid of experimental and clinical settings of acute lung injury. TNF-α administration to experimental animals increases pulmonary leukostasis, microvascular permeability and edema formation. Further, TNF-α can directly open the pulmonary vascular endothelial paracellular pathway in vitro. TNF-α opens the pulmonary endothelial paracellular pathway in both a dose- and time-dependent manner independent of endothelial cell injury/apoptosis. A prolonged stimulus-to-response lag time between the TNF-α stimulus and altered barrier function exists (≥2h) and this delayed response cannot be ascribed to a requirement for de novo protein synthesis. TNF-α activates one or more protein tyrosine kinase(s), increases tyrosine phosphorylation of adherens junction proteins, and induces actin disassembly temporally coincident with opening of the paracellular pathway; the increased protein tyrosine phosphorylation and actin reorganization are both prerequisites to TNF-α-induced loss of endothelial barrier function. Febrile range hyperthermia further enhances TNF-α levels and its biological effects. All of these data implicate TNF-α in the pathogenesis of acute lung injury. Understanding the mechanisms through which TNF-α regulates the pulmonary microvascular paracellular pathway should provide targets for future clinical interventions.

Respiratory sensation often occurs in patients suffering from acute or chronic respiratory and/or cardiac diseases, leading to dyspnoea. It is supported by the cortical integration of sensory pathways arising from the airways and lungs, respiratory muscles, and circulatory system. Their activation by direct electrical stimulation or circumstances mimicking pathological events (mechanical and less often chemical test agents) evokes cortical potentials and modifies the spontaneous EEG rhythms in cortical areas which also receive information from the skin, joints, and limb muscles. The quantification of respiratory sensation is obtained by psychophysical methods based on different theories linking the stimulus to its perception. Pathological or environmental circumstances act as triggers of the dyspnoea sensation. Ventilatory loading, elicited by dense gas breathing and mostly pathological airway obstruction, leads to an enhanced intrathoracic pressure and respiratory muscle work which in turn activate the vagal and respiratory muscle afferents. Experiments in healthy subjects testify for marked alterations of the tactile sensation and voluntary motor control to limb muscles when the respiratory system is loaded. These viscero-somatic interactions could partly support the well-known phenomenon of altered exercise performances and perception of the body image in patients suffering from chronic respiratory diseases, apart from any disturbances in respiratory gases.

Death is the outcome of tuberculosis most feared by patients and their families. The development of antituberculosis chemotherapy in the 1950s led to dramatic reductions in tuberculosis deaths in populations with access to treatment. The emergence of HIV in the 1980s reinstated tuberculosis as "a captain of the men of death" in countries with high HIV prevalence. The annual global toll of deaths among tuberculosis patients is currently about 2 million. Along with reducing morbidity and disease transmission, reducing tuberculosis deaths is one of the objectives of tuberculosis control. The world faces the challenge of reducing tuberculosis deaths by half by 2015, as part of achieving the United Nations Millennium Development Goals. Since HIV increases the risk of death during and after tuberculosis treatment, and is related to the degree of immunosuppression, the total number of deaths among tuberculosis patients is increased in populations with high HIV prevalence. Sub-Saharan Africa is the region most badly affected by the HIV epidemic and therefore also with the highest proportion of tuberculosis deaths attributable to HIV. Improvements in the routine reporting of deaths by national tuberculosis programmes will increase the utility of tuberculosis deaths as an indicator of programme performance. Improved epidemiological surveillance of tuberculosis mortality depends on investment in developing vital registration systems. Decreasing deaths among tuberculosis patients in countries with high HIV prevalence depends on measures to decrease tuberculosis incidence (by implementing the World Health Organization expanded strategy to control HIVrelated tuberculosis) and to decrease tuberculosis case fatality (e.g. health service improvements to decrease diagnostic delay, antiretroviral treatment, co-trimoxazole).

BK polyoma virus-associated hemorrhagic cystitis has been described in patients who have had renal, bone marrow and cardiac transplantation. We report the first case of hemorrhagic cystitis associated with the BK virus in a 51 year old woman with scleroderma, who received bilateral lung transplantation. The pathological findings of the bladder were large cells with enlarged nuclei and scant cytoplasm (Decoy cells). The diagnosis was confirmed by immunohistochemical stains of the urinary bladder tissue and by blood and urine PCR. The patient required a cystectomy.

Community-acquired pneumonia (CAP) is a relatively common and potentially serious infection that affects both immunocompetent and immunosuppressive adults throughout the world. The annual incidence of CAP in the United States is approximately 4 million cases. CAP due to atypical pathogens accounts for approximately 20 to 40 percent of cases necessitating hospitalization. There are few data regards to the prevalence rates of severe CAP due to atypical pathogens necessitating admission to the intensive care unit. This review article summarizes clinical features, diagnostic criteria, differential diagnosis, and management based on guidelines of medical societies.

CCAAT/enhancer binding proteins (C/EBPs) are key-regulators of cell differentiation and linked processes such as proliferation, apoptosis and gene expression in several organs. C/EBPs are also central for inflammatory responses and infectious defenses, but so far little is known of their role in lung diseases. However, a role for these intracellular proteins has recently been suggested in asthma, lung cancer and chronic bronchitis-COPD. In this mini-review, an overview of the biological roles of C/EBPs in lung is provided, together with a discussion of the recent studies suggesting a role for these transcription factors in the pathogenesis of some of our most common and severe lung diseases.

This article reviews research on acute inflammatory lung injury induced by gastric aspiration in animal models. The innate pulmonary inflammatory response and the severity of lung injury depend strongly on the nature of the gastric aspirate: hydrochloric acid (ACID, pH 1.25), small non-acidified gastric particles (SNAP), or combined acid and small gastric particles (CASP). The "two-hit" pathology of CASP aspiration in rodents is directly relevant for clinical gastric aspiration, and may lead to an increased risk for progression to clinical acute lung injury (ALI) or the acute respiratory distress syndrome (ARDS). Rodents (rats, mice) with CASP aspiration have more severe acute pulmonary injury based on decreased PaO2/FiO2 ratios and increased albumin levels in bronchoalveolar lavage (BAL) compared to rodents given ACID or SNAP alone. Rodents given CASP also have increased inflammation based on levels of cytokines and chemokines in BAL during the 48 hr period post-aspiration. Recent research has used hierarchical cluster analysis and statistical modeling to define more specific correlations between lavaged inflammatory mediators and lung injury severity in rodents with ACID, SNAP, and CASP aspiration. Studies in transgenic murine models (e.g., MCP-1 (-/-) mice) have also been done to help assess the functional importance of particular mediators in aspiration injury. In addition to reviewing the effects of "two-hit" aspirates like CASP, this article also describes research on combination injuries where a second injury inducer (hyperoxia, lung contusion from blunt chest trauma, or instilled E. coli bacteria) is present concurrently with gastric aspiration. The concept of multi-hit injury to the lungs has major clinical significance. A single insult such as acid aspiration may be relatively well tolerated by the pulmonary parenchyma, but the presence of a concurrent or subsequent second insult such as particulate aspiration, hyperoxia, or pulmonary bacterial infection may lead to profound respiratory dysfunction with physiological attributes of ALI/ARDS.

Lipopolysaccharide (LPS) inhalation challenge is emerging as an experimental system for modeling environmental airway disease such as that seen in agricultural workers, and it can also serve as a model of environmental asthma. Mice exposed chronically to LPS develop all of the classical features of asthma including reversible airflow obstruction and inflammation, persistent airway hyperreactivity (AHR), and airway remodeling. Thickening and fibrosis of the subepithelial region of the airway wall is a consistent histologic feature of both environmental airway disease and of asthma that is directly related to the clinical severity of the disease. Lessons learned from such model systems may help to identify mechanisms that are fundamental to the development of chronic environmental airway disease and asthma.

Cigarette smoking is the main risk factor for chronic obstructive pulmonary disease (COPD). However, not all smokers develop clinically significant symptoms. It is recognized that multiple genetic factors and genotype-byenvironment interactions are involved in the development of COPD. Remarkable progress in the genetic knowledge and technology has changed the approaches used to identify candidate genes. Genome-wide linkage analyses have revealed several chromosomal regions linked to COPD phenotypes. The recently introduced gene expression profiling techniques have identified hundreds of genes differentially expressed in COPD. Case-control association studies have reported more than 30 polymorphisms related to the susceptibility to COPD. However, the replication of these results has been limited. In this review, we present our current understanding of the genetic basis of COPD and the findings of genetic studies. The advantages and limitations of the different genetic approaches are also discussed. The increasing knowledge of the COPD genetics combined with a better understanding of its clinical and pathological heterogeneity will have a great potential to change views on the pathogenesis and diagnosis, and even to influence the clinical management.

Human immunodeficiency virus (HIV) infection first manifested itself as Acquired Immune Deficiency Syndrome (AIDS) in the early 1980s when young, previously healthy homosexual men presented with Pneumocystis carinii pneumonia (PCP). Since the discovery of HIV and AIDS, many different respiratory infections (common, uncommon and opportunistic), as well as different malignancies such as Kaposi's sarcoma, and destructive lung processes, such as emphysema have been shown to occur more commonly in the setting of HIV. Alterations in the CD4+/CD8+ lymphocyte composition and changes in the function of B cells compromise host defenses and predispose an HIV infected individual to respiratory infections. Highly Active Antiretroviral Therapy (HAART) has dramatically altered the course of HIV infection through suppression of viral replication, a reconstitution of CD4+ cells, and the resultant decrease in opportunistic infections, including PCP. This manuscript provides a contemporary review of the respiratory diseases of patients with HIV.

Radiation therapy is a widely used treatment for locally advanced non-small cell lung cancer, as well as for a variety of other thoracic malignancies. Radiation induced lung injury (RILI) refers to any lung-related change resulting from this treatment. From a clinical standpoint, RILI is separated into two distinct syndromes: an acute pneumonitis beginning 2-10 weeks following RT and a more indolent fibrotic process, presenting months after initial exposure. A variety of factors have been identified that are associated with an increased risk of developing clinically significant RILI. These include treatment-related factors (dose and schedule of radiation, volume of lung irradiated, concurrent use of chemotherapy) and patient-related factors (age, gender, smoking status, presence of pre-existing lung disease). New insights into the mechanisms of radiation induced lung injury have been uncovered, and these findings have led to the development of novel strategies for the prevention and treatment of this complication. In this review, we will discuss the clinical manifestations and risk factors of RILI, and focus on recent advances in its pathogenesis and treatment.

Recent findings show that the TGFβ peptide superfamily signaling pathway is not only essential for both prenatal and postnatal lung morphogenesis, but also plays a key role in the pathobiology of bronchopulmonary dysplasia, lung fibrosis and emphysema. Exquisitely tight regulation of TGFβ bioavailabilty and function is mediated at all levels of signal transduction from the extracelluar space to the nucleus. While the potential for therapeutic manipulation of TGFβ function is great, the practical application to pulmonary medicine will be exigent because of the requirement for exact modulation of TGFβ bioactivity and signaling within a very narrow physiological range.