In a recently performed case-control study, characteristics of the airway microbiota in suboptimally controlled adult asthmatics were compared to those of healthy, non-asthmatic adult subjects. Bacterial burden was significantly greater in asthmatic subjects. Further, increased airway microbiota variability and diversity were correlated with increased bronchial hyperresponsiveness. Though several limitations are present, this study provides an intriguing initial insight into the possible relationship between the airway microbiota and asthma pathogenesis.
Microbiota; bronchial hyperresponsiveness; bacterial infection; asthma; microarray; macrolides
Lymphangioleiomyomatosis (LAM), a multisystem disease predominantly affecting premenopausal women, is associated with cystic lung destruction and lymphatic and kidney tumors. LAM results from the proliferation of a neoplastic cell that has mutations in the tuberous sclerosis complex 1 or 2 genes, leading to activation of a critical regulatory protein, mammalian target of rapamycin. In this report, we discuss the molecular mechanisms regulating LAM cell growth and report the results of therapeutic trials employing new targeted agents. At present, inhibitors of mammalian target of rapamycin such as sirolimus appear to be the most promising therapeutic agents, although drug toxicity and development of resistance are potential problems. As the pathogenesis of LAM is being further recognized, other therapeutic agents such as matrix metalloproteinase inhibitors, statins, interferon, VEGF inhibitors, chloroquine analogs and cyclin-dependent kinase inhibitors, along with sirolimus or a combination of several of these agents, may offer the best hope for effective therapy.
chylous effusions; lung function decline; lymphangioleiomyomas; lymphangioleiomyomatosis; sirolimus; tuberous sclerosis complex
In 2010, 1770 lung transplant procedures were performed in the USA, yet 2469 new candidates were added to the waiting list the same year. The shortage of suitable donor lungs requires that transplant professionals select patients for lung transplantation only if they are likely to sustain a survival benefit from the procedure. However, 20% of lung transplant recipients die within the first year of transplantation, suggesting that we are failing to identify those at high risk for severe early complications. In this perspective, we review the current guidelines for the selection of lung transplant candidates, which are based largely on expert opinion and small case series. We also propose the study of new extrapulmonary factors, such as frailty and sarcopenia, that might help improve the prediction of complications and early death after lung transplantation, leading to an improved candidate selection process.
chronic obstructive pulmonary disease; frailty; interstitial lung disease; lung transplantation; obesity; pulmonary arterial hypertension; sarcopenia
In children under 5 years of age, human parainfluenza viruses (HPIVs) as a group are the second most common etiology of acute respiratory illness leading to hospitalization, surpassed only by respiratory syncytial virus but ahead of influenza viruses. Using reverse genetics systems for HPIV serotypes 1, 2 and 3 (HPIV1, 2 and 3), several live-attenuated HPIVs have been generated and evaluated as intranasal vaccines in adults and in children. Two vaccines against HPIV3 were found to be well tolerated, infectious and immunogenic in Phase I trials in HPIV3-seronegative infants and children and should progress to proof-of-concept trials. Vaccines against HPIV1 and HPIV2 are less advanced and have just entered pediatric trials.
acute respiratory illness; clinical trial; intranasal; live-attenuated; parainfluenza virus vaccine; pediatric; vaccine
Nanoparticle drug-delivery systems offer the potential for improved efficacy of treatment, and yet there are also potential risks associated with these novel therapeutic strategies. An attractive property of carbon nanotubes (CNTs) is that the tube- or fiber-like structure allows for extensive functionalization and loading of cargo. However, a large body of evidence indicates that CNTs may have adverse effects if used in drug delivery as they have been shown to cause pulmonary fibrosis and exacerbate lung disease in rodents with pre-existing lung diseases. Major factors that cause these toxic effects are the high aspect ratio, durability and residual metal content that generate reactive oxygen species. Therefore, careful consideration should be given to the possibility that lung inflammation or fibrosis could be significant side effects caused by a CNT-based drug-delivery system, thereby outweighing any potential beneficial effects of therapeutic treatment. However, functionalization of CNTs to modulate aspect ratio, biodegradability and to remove residual metals could allow for safe design of CNTs for use in drug delivery in certain circumstances.
carbon nanotubes; disease risk; drug delivery; health benefits; nanoparticles
Airway smooth muscle (ASM) manifests a hyper-responsive phenotype in airway disorders such as asthma. ASM also modulates immune responses by secreting mediators and expressing cell-surface molecules that promote recruitment of inflammatory cells to the lungs. The aim of the current article is to highlight therapeutics that may modulate ASM responses in airway disorders and exacerbations.
antibody therapy; asthma; bronchial thermoplasty; exacerbation; remodeling
Until recently, relationships between evidence of colonization or infection by specific microbial species and the development, persistence or exacerbation of pulmonary disease have informed our opinions of airway microbiology. However, recent applications of culture-independent tools for microbiome profiling have revealed a more diverse microbiota than previously recognized in the airways of patients with chronic pulmonary disease. New evidence indicates that the composition of airway microbiota differs in states of health and disease and with severity of symptoms and that the microbiota, as a collective entity, may contribute to pathophysiologic processes associated with chronic airway disease. Here, we review the evolution of airway microbiology studies of chronic pulmonary disease, focusing on asthma, chronic obstructive pulmonary disease and cystic fibrosis. Building on evidence derived from traditional microbiological approaches and more recent culture-independent microbiome studies, we discuss the implications of recent findings on potential microbial determinants of respiratory health or disease.
16S ribosomal RNA; asthma; COPD; cystic fibrosis; microbiota; next-generation sequencing; PhyloChip
Children with sickle cell disease (SCD) and a comorbid condition of asthma have increased numbers of vaso-occlusive pain and acute chest syndrome episodes, and all-cause mortality. When assessed systematically, asthma prevalence is probably similar among children with SCD when compared with the general African–American population. With increasing recognition of the importance of asthma in the management of SCD, hematologists must become familiar with asthma and develop a multidisciplinary approach, including early recognition, appropriate management and referral to asthma specialists.
acute chest syndrome; asthma; bronchial hyper-reactivity; bronchodilator response; pulmonary function tests; sickle cell disease; sickle cell pain
Simian virus 40 (SV40) is a DNA virus isolated in 1960 from contaminated polio vaccines, that induces mesotheliomas, lymphomas, brain and bone tumors, and sarcomas, including osteosarcomas, in hamsters. These same tumor types have been found to contain SV40 DNA and proteins in humans. Mesotheliomas and brain tumors are the two tumor types that have been most consistently associated with SV40, and the range of positivity has varied about from 6 to 60%, although a few reported 100% of positivity and a few reported 0%. It appears unlikely that SV40 infection alone is sufficient to cause human malignancy, as we did not observe an epidemic of cancers following the administration of SV40-contaminated vaccines. However, it seems possible that SV40 may act as a cofactor in the pathogenesis of some tumors. In vitro and animal experiments showing cocarcinogenicity between SV40 and asbestos support this hypothesis.
brain tumor; malignant mesothelioma; SV40; Tag; tag; transformation
There have been many advances in the field of diagnostic and therapeutic pulmonary medicine in the past several years, with major progress in the field of imaging. Optical coherence tomography (OCT) is a high-resolution (micron level) imaging modality currently being advanced with the potential to image airway wall structures in real time and at higher resolution than previously possible. OCT has the potential to increase the sensitivity and specificity of biopsies, create 3D images of the airway to guide diagnostics, and may have a future role in diverse areas such as the evaluation and treatment of patients with obstructive sleep apnea, tracheal stenosis, airway remodeling and inhalation injury. OCT has recently been investigated to monitor airway compliance in chronic obstructive pulmonary disease and asthma patients as well as differentiate causes of pulmonary hypertension. In future clinical and research applications, OCT will likely be combined with other endoscopic based modalities such as ultrasound, spectroscopy, confocal, and/or photoacoustic tomography to determine functional and biomolecular properties. This article discusses the current uses of OCT, its potential applications, as it relates to specific pulmonary diseases, and the future directions for OCT.
imaging; multimodal; OCT; optical coherence tomography; optics; pulmonary advances; spectroscopy
Tissue regeneration and repair are fundamental both to recovery of the lung from injury and to the pathology of many chronic lung diseases. There are two potential sources for the adult progenitor cells that participate in this reparative process: resident lung progenitors and bone marrow-derived circulating cells. Bone marrow-derived cells, in particular, have been shown to give rise to airway and alveolar epithelial cells as well as lung mesenchymal cells. Emerging data has linked specific chemokine ligand-receptor interactions to the recruitment of these cells to the lung, and has implicated these cells in chronic lung disorders such as asthma and interstitial lung diseases. In this review, we summarize the current understanding of the biology of adult circulating progenitors as related to lung disease.
stem cells; fibrocytes; chemokines; regeneration
Systemic sclerosis (SSc) is commonly complicated by pulmonary arterial hypertension (PAH), which is a leading cause of death in the SSc patient population. Owing to the fact that the risk of developing pulmonary hypertension is high, screening is important, although the optimal modality remains to be defined. Furthermore, despite recent advances in therapy for PAH, the response to these interventions in patients with PAH with SSc has been discouraging. The lack of clinical response to these therapies may merely reflect the limitations of traditionally employed PAH outcome measures in SSc-PAH patients or highlight the heterogeneity of the disease manifestations within SSc. Importantly, since extrapulmonary involvement of the GI tract and kidneys by SSc limit candidacy for lung transplantation, new therapies that target abnormal cellular proliferation in the pulmonary vasculature are currently under investigation and may be particularly relevant to SSc-PAH.
diagnosis; pulmonary hypertension; systemic sclerosis; therapy
Pulmonary arterial hypertension is a disease characterized by a sustained increase in pulmonary arterial pressure leading to right heart failure. Current treatments focus on endothelial dysfunction and an aberrant regulatory pathway for vascular tone. Unfortunately, a large proportion of patients are unresponsive to conventional vasodilator therapy. Investigations are ongoing into the effects of experimental therapies targeting the signal transduction pathway that mediates vasodilation. Here, we briefly discuss the pathophysiology of pulmonary hypertension and endothelial dysfunction, along with current treatments. We then present a focused review of recent animal studies and human trials examining the use of activators and stimulators of soluble guanylate cyclase for the treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension.
activators; endothelial dysfunction; nitric oxide; pulmonary hypertension; soluble guanylate cyclase; stimulators
At present, therapeutic interventions to treat acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) remain largely limited to lung-protective strategies, as no real molecular–pathophysiologic-driven therapeutic intervention has yet become available. This is in part the result of the heterogeneous nature of the etiological processes that contribute to the state of ALI/ARDS. This article sets out to understand the development of ALI resulting from indirect pulmonary insults, such as extrapulmonary sepsis and trauma, shock, burn injury or mass transfusion, as opposed to direct pulmonary challenges, such as pneumonia, aspiration or lung contusion. Here, we consider not only the experimental and clinical data concerning the roles of various immune (neutrophil, macrophage, lymphocyte and dendritic) as well as nonimmune (epithelial and endothelial) cells in orchestrating the development of ALI resulting from indirect pulmonary stimuli, but also how these cell populations might be targeted therapeutically.
apoptosis; ARDS; Fas; silencing; small interfering RNA
Idiopathic pulmonary fibrosis (IPF) is a disease of unknown origin and progression that primarily affects older adults. Accumulating clinical and experimental evidence suggests that viral infections may play a role, either as agents that predispose the lung to fibrosis or exacerbate existing fibrosis. In particular, herpesviruses have been linked with IPF. This article summarizes the evidence for and against viral cofactors in IPF pathogenesis. In addition, we review mechanistic studies in animal models that highlight the fibrotic potential of viral infection, and explore the different mechanisms that might be responsible. We also review early evidence to suggest that the aged lung may be particularly susceptible to viral-induced fibrosis and make recommendations for future research directions.
collagen; Epstein-Barr virus; gammaherpesvirus; lung; murine gammaherpesvirus-68; senescence
Despite significant advances in our understanding of the pathophysiology of acute lung injury, a lung-protective strategy of mechanical ventilation remains the only therapy with a proven survival advantage. Numerous pharmacologic therapies have failed to show benefit in multicenter clinical trials. The paradigm of early, goal-directed therapy of sepsis suggests greater clinical benefit may derive from initiating therapy prior to the onset of respiratory failure that requires mechanical ventilation. Thus, there is heightened interest in more accurate and complete characterization of high-risk patient populations and identification of patients in the early stage of acute lung injury, prior to the need for mechanical ventilation. This article discusses the growing literature on clinical predictors of acute lung injury (including risk factors for specific subgroups) with an emphasis on transfusion-related risk factors and recent research targeting the early identification of high-risk patients and those with early acute lung injury prior to the onset of respiratory failure.
acute lung injury; acute respiratory distress syndrome; mechanical ventilation; noninvasive ventilation; pulmonary edema; risk factors; surgery; transfusion-related lung injury; trauma
Claiming more than 150,000 lives each year, lung cancer is the deadliest cancer in the USA. First-line treatments in lung cancer include surgical resection and chemotherapy, the latter of which offers only modest survival benefits at the expense of often severe and debilitating side effects. Recent advances in elucidating the molecular biology of lung carcinogenesis have elucidated novel drug targets, and treatments are rapidly evolving into specialized agents that hone in on specific aspects of the disease. Of particular interest is blocking tumor growth by targeting the physiological processes surrounding angiogenesis, pro-tumorigenic growth factor activation, anti-apoptotic cascades and other cancer-promoting signal transduction events. This article looks at several areas of interest to lung cancer therapeutics and considers the current state of affairs surrounding the development of these therapies.
angiogenesis; apoptosis; cancer stem cells; lung cancer; monoclonal antibody; signal transduction; targeted therapy; TKI; tyrosine kinase inhibitor
The molecular and cellular mechanisms underlying the pathogenesis of chronic obstructive pulmonary disease (COPD) remain incompletely understood. We have investigated the potential role of macro-autophagy, a cellular homeostatic mechanism, in COPD and cigarette smoke-induced lung-cell injury. Autophagy is a dynamic process for the turnover of organelles and proteins, which regenerates metabolic precursors through the lysosomal-dependent catabolism of cellular macromolecules. It is typically associated with survival pathways, especially in nutrient deficiency states. The role of autophagy in human diseases is less clear, and has been associated with both protective and detrimental consequences, depending on the disease model. While autophagy is considered cytoprotective, this process is often found in association with cell death, and the relationships between autophagy and cell death remain ambiguous. We have found elevated autophagy in COPD lung specimens, as well as in response to cigarette smoke exposure in vitro and in vivo. In our studies, the activation of autophagic proteins was associated with epithelial cell apoptosis in response to cigarette smoke, with pathogenic implications in COPD. Further studies are needed to determine the functional significance of autophagy in COPD and other diseases of the lung.
apoptosis; autophagy; chronic obstructive pulmonary disease; cigarette smoke; emphysema
The incidence of lung cancer in females is increasing, in contrast to that seen in males. In addition, the proportion of lung cancer cases in women attributable to smoking is approximately half of that seen in males. Female sex hormones, especially estrogen, may play a key role in this. Estrogen receptors ERα and ERβ have been detected on lung cancer cells and there is new evidence suggesting that hormone-replacement therapy may increase both the incidence of, and mortality from, lung cancer in women. Laboratory evidence lends credence to the carcinogenic effects of estrogens in lung cancer. This article summarizes the current evidence on their role in lung cancer.
estrogen; estrogen receptors; fulvestrant; hormone-replacement therapy; lung cancer; women
Neurotrophins (NTs) are a family of growth factors that are well-known in the nervous system. There is increasing recognition that NTs (nerve growth factor, brain-derived neurotrophic factor and NT3) and their receptors (high-affinity TrkA, TrkB and TrkC, and low-affinity p75NTR) are expressed in lung components including the nasal and bronchial epithelium, smooth muscle, nerves and immune cells. NT signaling may be important in normal lung development, developmental lung disease, allergy and inflammation (e.g., rhinitis, asthma), lung fibrosis and even lung cancer. In this review, we describe the current status of our understanding of NT signaling in the lung, with hopes of using aspects of the NT signaling pathway in the diagnosis and therapy of lung diseases.
asthma; bronchopulmonary dysplasia; development; fibrosis; inflammation; lung cancer; neurotrophic factor; rhinitis
Although mechanical ventilation (MV) is a life-saving intervention for patients with acute respiratory distress syndrome (ARDS), it can aggravate or cause lung injury, known as ventilator-induced lung injury (VILI). The biophysical characteristics of heterogeneously injured ARDS lungs increase the parenchymal stress associated with breathing, which is further aggravated by MV. Cells, in particular those lining the capillaries, airways and alveoli, transform this strain into chemical signals (mechanotransduction). The interaction of reparative and injurious mechanotransductive pathways leads to VILI. Several attempts have been made to identify clinical surrogate measures of lung stress/strain (e.g., density changes in chest computed tomography, lower and upper inflection points of the pressure–volume curve, plateau pressure and inflammatory cytokine levels) that could be used to titrate MV. However, uncertainty about the topographical distribution of stress relative to that of the susceptibility of the cells and tissues to injury makes the existence of a single ‘global’ stress/strain injury threshold doubtful.
acute lung injury; acute respiratory distress syndrome; esophageal pressure; lung strain; lung stress; mechanical ventilation; mechanotransduction; plateau pressure; ventilator-induced lung injury
Respiratory infections are associated with wheezing illnesses in all ages and may also impact the development and severity of asthma. Respiratory tract infections caused by viruses, Chlamydophila or Mycoplasma have been hypothesized to have significant roles in the pathogenesis of asthma. Progress is being made toward establishing the mechanisms by which these agents can cause acute wheezing and impact the pathophysiology of asthma. Host factors probably contribute to the risk of asthma inception and exacerbation, and these contributions may also vary with respect to early- versus adult-onset disease. This review discusses these various associations as they pertain to the development and exacerbation of asthma.
asthma; asthma inception; exacerbation; respiratory infection; virus
Pulmonary edema occurs when fluid flux into the lung interstitium exceeds its removal, resulting in hypoxemia and even death. Noncardiogenic pulmonary edema (NPE) generally results when microvascular and alveolar permeability to plasma proteins increase, one possible etiology being oxidant injury. Reactive oxygen and nitrogen species (RONS) can modify or damage ion channels, such as epithelial sodium channels, which alters fluid balance. Experimental systems in which either RONS are increased or protective antioxidant mechanisms are decreased result in alterations of epithelial sodium channel activity and support the hypothesis that RONS are important in NPE. Both basic and clinical studies are needed to critically define the RONS–NPE connection and the capacity of antioxidant therapy (either alone or as a supplement to β-agonists) to improve patient outcome.
antioxidants; free radicals; pulmonary edema; reactive oxygen and nitrogen species; RONS; sodium transport
Smoke inhalation injury continues to increase morbidity and mortality in burn patients in both the third world and industrialized countries. The lack of uniform criteria for the diagnosis and definition of smoke inhalation injury contributes to the fact that, despite extensive research, mortality rates have changed little in recent decades. The formation of reactive oxygen and nitrogen species, as well as the procoagulant and antifibrinolytic imbalance of alveolar homeostasis, all play a central role in the pathogenesis of smoke inhalation injury. Further hallmarks include massive airway obstruction owing to cast formation, bronchospasm, the increase in bronchial circulation and transvascular fluid flux. Therefore, anticoagulants, antioxidants and bronchodilators, especially when administered as an aerosol, represent the most promising treatment strategies. The purpose of this review article is to provide an overview of the pathophysiological changes, management and treatment options of smoke inhalation injury based on the current literature.
acute lung injury; anticoagulants; antioxidants; β2-agonists; carbon monoxide; cyanide; nitric oxide; reactive oxygen species
Pulmonary arterial hypertension (PAH), a common complication of systemic sclerosis, carries a very severe prognosis and is one of the leading causes of death in patients who suffer from it. Indeed, response to modern medical therapy has been disappointing in scleroderma-related PAH compared with other forms of PAH from the WHO group 1 classification of diseases, despite similar histological changes involving the pulmonary vasculature. This review discusses specific features of scleroderma-related PAH, currently available and US FDA-approved therapy for this syndrome, as well as potential future therapeutic developments based on newly acquired knowledge of this disorder.
endothelin receptor antagonist; phosphodiesterase inhibitor; prostaglandin; pulmonary arterial hypertension; scleroderma; therapy