搜索结果：Experimental lung research

1 From the Departments of Epidemiology and Health, and of Experimental Medicine, McGill University, and from the Department of Medicine, Royal Victoria Hospital, Montreal, Quebec, Canada. 2 Requests for reprints should l.>e addressed to Department of Epidemiology and Health, McGill University, 3775 University Street, Montreal, Quebec, Canada. 3 Associate of the Medical Research Council of Canada. Pathology Pathogenesis Clinical Features Radiographic Changes Lung Function Diagnosis Prognosis, Complications, and Medical Management

Recently, many researchers paid more attentions to the association between air pollution and respiratory system disease. In the past few years, levels of smog have increased throughout China resulting in the deterioration of air quality, raising worldwide concerns. PM2.5 (particles less than 2.5 micrometers in diameter) can penetrate deeply into the lung, irritate and corrode the alveolar wall, and consequently impair lung function. Hence it is important to investigate the impact of PM2.5 on the respiratory system and then to help China combat the current air pollution problems. In this review, we will discuss PM2.5 damage on human respiratory system from epidemiological, experimental and mechanism studies. At last, we recommend to the population to limit exposure to air pollution and call to the authorities to create an index of pollution related to health.

Lung volumes are subdivided into static and dynamic lung volumes. Static lung volumes are measured by methods which are based on the completeness of respiratory manoeuvres, so that the velocity of the manoeuvres should be adjusted accordingly. The measurements taken during fast breathing movements are described as dynamic lung volumes and as forced inspiratory and expiratory flows. ### 1.1 Static lung volumes and capacities The volume of gas in the lung and intrathoracic airways is determined by the properties of lung parenchyma and surrounding organs and tissues, surface tension, the force exerted by respiratory muscles, by lung reflexes and by the properties of airways. The gas volumes of thorax and lung are the same except in the case of a pneumothorax. If two or more subdivisions of the total lung capacity are taken together, the sum of the constituent volumes is described as a lung capacity. Lung volumes and capacities are described in more detail in § 2. #### 1.1.1 Determinants Factors which determine the size of the normal lung include stature, age, sex, body mass, posture, habitus, ethnic group, reflex factors and daily activity pattern. The level of maximal inspiration (total lung capacity, TLC) is influenced by the force developed by the inspiratory muscles (disorders include e.g. muscular dystrophy), the elastic recoil of the lung (disorders include e.g. pulmonary fibrosis and emphysema) and the elastic properties of the thorax and adjacent structures (disorders include e.g. ankylosis of joints). The level of maximal expiration (residual volume, RV) is determined by the force exerted by respiratory muscles (disorders include e.g. muscle paralysis), obstruction, occlusion and compression of small airways (disorders include e.g. emphysema) and by the mechanical properties of lung and thorax (disorders include diffuse fibrosis, kyphoscoliosis). Assessing the total lung capacity is indispensable in establishing a restrictive ventilatory defect or in diagnosing abnormal lung distensibility, as may occur in patients …

The lung microbiome is associated with host immune response and health outcomes in experimental models and patient cohorts. Lung microbiome research is increasing in volume and scope; however, there are no established guidelines for study design, conduct, and reporting of lung microbiome studies. Standardized approaches to yield reliable and reproducible data that can be synthesized across studies will ultimately improve the scientific rigor and impact of published work and greatly benefit microbiome research. In this review, we identify and address several key elements of microbiome research: conceptual modeling and hypothesis framing; study design; experimental methodology and pitfalls; data analysis; and reporting considerations. Finally, we explore possible future directions and research opportunities. Our goal is to aid investigators who are interested in this burgeoning research area and hopefully provide the foundation for formulating consensus approaches in lung microbiome research.

OBJECTIVE: We tested whether the continuous monitoring of dynamic compliance could become a useful bedside tool for detecting the beginning of collapse of a fully recruited lung. DESIGN: Prospective laboratory animal investigation. SETTING: Clinical physiology research laboratory, University of Uppsala, Sweden. SUBJECTS: Eight pigs submitted to repeated lung lavages. INTERVENTIONS: Lung recruitment maneuver, the effect of which was confirmed by predefined oxygenation, lung mechanics, and computed tomography scan criteria, was followed by a positive end-expiratory pressure (PEEP) reduction trial in a volume control mode with a tidal volume of 6 mL/kg. Every 10 mins, PEEP was reduced in steps of 2 cm H2O starting from 24 cm H2O. During PEEP reduction, lung collapse was defined by the maximum dynamic compliance value after which a first measurable decrease occurred. Open lung PEEP according to dynamic compliance was then defined as the level of PEEP before the point of collapse. This value was compared with oxygenation (Pao2) and CT scans. MEASUREMENTS AND MAIN RESULTS: Pao2 and dynamic compliance were monitored continuously, whereas computed tomography scans were obtained at the end of each pressure step. Collapse defined by dynamic compliance occurred at a PEEP of 14 cm H2O. This level coincided with the oxygenation-based collapse point when also shunt started to increase and occurred one step before the percentage of nonaerated tissue on the computed tomography exceeded 5%. Open lung PEEP was thus at 16 cm H2O, the level at which oxygenation and computed tomography scan confirmed a fully open, not yet collapsed lung condition. CONCLUSIONS: In this experimental model, the continuous monitoring of dynamic compliance identified the beginning of collapse after lung recruitment. These findings were confirmed by oxygenation and computed tomography scans. This method might become a valuable bedside tool for identifying the level of PEEP that prevents end-expiratory collapse.

A complete understanding of how exposure to environmental substances promotes cancer formation is lacking. More than 70 years ago, tumorigenesis was proposed to occur in a two-step process: an initiating step that induces mutations in healthy cells, followed by a promoter step that triggers cancer development1. Here we propose that environmental particulate matter measuring ≤2.5 μm (PM2.5), known to be associated with lung cancer risk, promotes lung cancer by acting on cells that harbour pre-existing oncogenic mutations in healthy lung tissue. Focusing on EGFR-driven lung cancer, which is more common in never-smokers or light smokers, we found a significant association between PM2.5 levels and the incidence of lung cancer for 32,957 EGFR-driven lung cancer cases in four within-country cohorts. Functional mouse models revealed that air pollutants cause an influx of macrophages into the lung and release of interleukin-1β. This process results in a progenitor-like cell state within EGFR mutant lung alveolar type II epithelial cells that fuels tumorigenesis. Ultradeep mutational profiling of histologically normal lung tissue from 295 individuals across 3 clinical cohorts revealed oncogenic EGFR and KRAS driver mutations in 18% and 53% of healthy tissue samples, respectively. These findings collectively support a tumour-promoting role for PM2.5 air pollutants and provide impetus for public health policy initiatives to address air pollution to reduce disease burden. Combination of epidemiology, preclinical models and ultradeep DNA profiling of clinical cohorts unpicks the inflammatory mechanism by which air pollution promotes lung cancer

In the United States, the 20th century witnessed the emergence of a lung cancer epidemic that peaked and began to decline by the century's end, a decline that continues today. However, lung cancer continues to be an unabating pandemic. In research carried out over the last half of the 20th century, many factors were causally associated with lung cancer and studies were implemented to identify determinants of susceptibility to these factors. Cigarette smoking was identified as the single most predominant cause of the lung cancer epidemic, but other causes were found, including workplace agents (eg, asbestos, arsenic, chromium, nickel, and radon) and other environmental factors (passive smoking, indoor radon, and air pollution). Contemporary epidemiologic research on lung cancer now focuses on a new set of issues, primarily related to susceptibility to the well-identified causal factors, particularly smoking, and on the consequences of changes in tobacco products for risks to smokers. Diet and the possibility of reducing risk through chemoprevention remain a focus of research emphasis through experimental and observational approaches. Questions have also been raised about possible differences in susceptibility to lung cancer by sex and race. Population patterns in smoking prevalence will continue to be the most powerful predictor of the future occurrence of lung cancer. Evaluation of recent US patterns in smoking prevalence indicates that for the next approximately 10 to 15 years, lung cancer rates will decrease, but will then level off starting in approximately 2030. Unless further reductions in the prevalence of cigarette smoking are achieved over the next decade, lung cancer will remain as an all too common, but avoidable, disease.

Muggia and Rozenweig have done a good job of compiling a book that provides an overview of the current research effort in the treatment of lung cancer. The book is divided into nine parts that review the current research in experimental animal tumor models of lung cancer, pathological diagnosis, biologic markers, surgery, radiotherapy, chemotherapy in established disease as well as in an adjuvant setting, immunotherapy, and the therapeutic approach to small cell carcinoma. There are some exceptionally good sections in this book that should be required reading for medical oncologists; these include the chapters on experimental tumors, pathological diagnosis, Mountain's chapter on the surgical approach, and the treatment of small cell carcinoma. However, the section on biological markers was weak and of little relevance to the diagnosis, prognosis, or treatment of lung cancer. Since many of the sections were written by various authors, the style and presentation of data varies;

OBJECTIVE: We investigated whether potentially injurious transpulmonary pressure could be generated by strong spontaneous breathing and exacerbate lung injury even when plateau pressure is limited to <30 cm H2O. DESIGN: Prospective, randomized, animal study. SETTING: University animal research laboratory. SUBJECTS: Thirty-two New Zealand White rabbits. INTERVENTIONS: Lavage-injured rabbits were randomly allocated to four groups to receive low or moderate tidal volume ventilation, each combined with weak or strong spontaneous breathing effort. Inspiratory pressure for low tidal volume ventilation was set at 10 cm H2O and tidal volume at 6 mL/kg. For moderate tidal volume ventilation, the values were 20 cm H2O and 7-9 mL/kg. The groups were: low tidal volume ventilation+spontaneous breathingweak, low tidal volume ventilation+spontaneous breathingstrong, moderate tidal volume ventilation+spontaneous breathingweak, and moderate tidal volume ventilation+spontaneous breathingstrong. Each group had the same settings for positive end-expiratory pressure of 8 cm H2O. MEASUREMENTS AND RESULTS: Respiratory variables were measured every 60 mins. Distribution of lung aeration and alveolar collapse were histologically evaluated. Low tidal volume ventilation+spontaneous breathingstrong showed the most favorable oxygenation and compliance of respiratory system, and the best lung aeration. By contrast, in moderate tidal volume ventilation+spontaneous breathingstrong, the greatest atelectasis with numerous neutrophils was observed. While we applied settings to maintain plateau pressure at <30 cm H2O in all groups, in moderate tidal volume ventilation+spontaneous breathingstrong, transpulmonary pressure rose >33 cm H2O. Both minute ventilation and respiratory rate were higher in the strong spontaneous breathing groups. CONCLUSIONS: Even when plateau pressure is limited to <30 cm H2O, combined with increased respiratory rate and tidal volume, high transpulmonary pressure generated by strong spontaneous breathing effort can worsen lung injury. When spontaneous breathing is preserved during mechanical ventilation, transpulmonary pressure and tidal volume should be strictly controlled to prevent further lung injury.

Epithelial-mesenchymal transition (EMT) encompasses dynamic changes in cellular organization from epithelial to mesenchymal phenotypes, which leads to functional changes in cell migration and invasion. EMT occurs in a diverse range of physiological and pathological conditions and is driven by a conserved set of inducing signals, transcriptional regulators and downstream effectors. With over 5,700 publications indexed by Web of Science in 2019 alone, research on EMT is expanding rapidly. This growing interest warrants the need for a consensus among researchers when referring to and undertaking research on EMT. This Consensus Statement, mediated by 'the EMT International Association' (TEMTIA), is the outcome of a 2-year-long discussion among EMT researchers and aims to both clarify the nomenclature and provide definitions and guidelines for EMT research in future publications. We trust that these guidelines will help to reduce misunderstanding and misinterpretation of research data generated in various experimental models and to promote cross-disciplinary collaboration to identify and address key open questions in this research field. While recognizing the importance of maintaining diversity in experimental approaches and conceptual frameworks, we emphasize that lasting contributions of EMT research to increasing our understanding of developmental processes and combatting cancer and other diseases depend on the adoption of a unified terminology to describe EMT.

Lung cancer is the primary cause of mortality in the United States and around the globe. Therapeutic options for lung cancer treatment include surgery, radiation therapy, chemotherapy, and targeted drug therapy. Medical management is often associated with the development of treatment resistance leading to relapse. Immunotherapy is profoundly altering the approach to cancer treatment owing to its tolerable safety profile, sustained therapeutic response due to immunological memory generation, and effectiveness across a broad patient population. Different tumor-specific vaccination strategies are gaining ground in the treatment of lung cancer. Recent advances in adoptive cell therapy (CAR T, TCR, TIL), the associated clinical trials on lung cancer, and associated hurdles are discussed in this review. Recent trials on lung cancer patients (without a targetable oncogenic driver alteration) reveal significant and sustained responses when treated with programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) checkpoint blockade immunotherapies. Accumulating evidence indicates that a loss of effective anti-tumor immunity is associated with lung tumor evolution. Therapeutic cancer vaccines combined with immune checkpoint inhibitors (ICI) can achieve better therapeutic effects. To this end, the present article encompasses a detailed overview of the recent developments in the immunotherapeutic landscape in targeting small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Additionally, the review also explores the implication of nanomedicine in lung cancer immunotherapy as well as the combinatorial application of traditional therapy along with immunotherapy regimens. Finally, ongoing clinical trials, significant obstacles, and the future outlook of this treatment strategy are also highlighted to boost further research in the field.

Lung cancer is the most frequent malignant neoplasm in most countries, and the main cancer-related cause of mortality worldwide in both sexes combined.The geographic and temporal patterns of lung cancer incidence, as well as lung cancer mortality, on a population level are chiefly determined by tobacco consumption, the main aetiological factor in lung carcinogenesis.Other factors such as genetic susceptibility, poor diet, occupational exposures and air pollution may act independently or in concert with tobacco smoking in shaping the descriptive epidemiology of lung cancer. Moreover, novel approaches in the classification of lung cancer based on molecular techniques have started to bring new insights to its aetiology, in particular among nonsmokers. Despite the success in delineation of tobacco smoking as the major risk factor for lung cancer, this highly preventable disease remains among the most common and most lethal cancers globally.Future preventive efforts and research need to focus on non-cigarette tobacco smoking products, as well as better understanding of risk factors underlying lung carcinogenesis in never-smokers.

Despite the grave difficulties that beset researchers who are trying to isolate and characterize the various intracellular and extracellular forms of lung surfactant; despite the serious ambiguities of interpretation of experimental data caused by the multicomponent nature of the surfactant; despite the inaccessibility for diagnostic purposes of this material, which functions deep in the lungs; despite the fact that incisive methods of protein chemistry and molecular biology have only recently been brought to bear on lung surfactant; despite all these problems, our knowledge and understanding of lung surfactant are rapidly increasing. We know now that it is a dynamic system with many parts, and that the reserves of these are normally not large and are recycled. We believe that tight metabolic control must exist to maintain these reserves, and we already have experimental techniques to raise or lower the reserves. Heroic methods of surfactant substitution are now being tested in patients whose deficiency or risk thereof is sufficiently desperate, and the results of these clinical trials, if they are carefully documented with lung function data, will add a new dimension to our knowledge of surfactant dynamics. We may expect in the future that more subtle alterations in surfactant function will become detectable and more sophisticated methods to manipulate the system will be invented. Essential to these will be a deeper understanding of surfactant forms, pathways, kinetics, and controls. Fortunately, research on surfactant structure, metabolism, and turnover intrigues many investigators. They, we may hope, will soon provide the necessary information.

A wide-ranging overview of genetic alterations in lung adenocarcinomas, published in this issue, takes a new approach to genome analysis. The analysis of 371 tumours revealed 31 recurrent focal events, only six of which were known previously in lung carcinomas. A new candidate oncogene, TITF1, was found to be significant in a large number of lung cancers. This work shows that there are many more important cancer-related genes still undiscovered, and that systematic genomic study can reveal them. A large-scale study that analyses gene copy number changes in lung cancer identifies 31 recurrent focal events, which include amplification of the transcription factor NKX2.1 (also called TTF1), shown to act as an oncogene. Somatic alterations in cellular DNA underlie almost all human cancers1. The prospect of targeted therapies2 and the development of high-resolution, genome-wide approaches3,4,5,6,7,8 are now spurring systematic efforts to characterize cancer genomes. Here we report a large-scale project to characterize copy-number alterations in primary lung adenocarcinomas. By analysis of a large collection of tumours (n = 371) using dense single nucleotide polymorphism arrays, we identify a total of 57 significantly recurrent events. We find that 26 of 39 autosomal chromosome arms show consistent large-scale copy-number gain or loss, of which only a handful have been linked to a specific gene. We also identify 31 recurrent focal events, including 24 amplifications and 7 homozygous deletions. Only six of these focal events are currently associated with known mutations in lung carcinomas. The most common event, amplification of chromosome 14q13.3, is found in ∼12% of samples. On the basis of genomic and functional analyses, we identify NKX2-1 (NK2 homeobox 1, also called TITF1), which lies in the minimal 14q13.3 amplification interval and encodes a lineage-specific transcription factor, as a novel candidate proto-oncogene involved in a significant fraction of lung adenocarcinomas. More generally, our results indicate that many of the genes that are involved in lung adenocarcinoma remain to be discovered.

Lung cancer is the leading cause of global cancer incidence and mortality, accounting for an estimated 2 million diagnoses and 1.8 million deaths. Neoplasms of the lungs are the second most common cancer diagnosis in men and women (after prostate and breast cancer, respectively). With increasing access to tobacco and industrialization in developing nations, lung cancer incidence is rising globally. The average age of diagnosis is 70 years old. Men are twice as likely to be diagnosed with lung cancer, which largely reflects differences in tobacco consumption, although women may be more susceptible due to higher proportions of epidermal growth factor receptor mutations and the effects of oestrogen. African American men in the US are at the highest risk of lung cancer. Family history increases risk by 1.7-fold, with a greater risk among first-degree relatives. Tobacco smoking is the greatest preventable cause of death worldwide, accounting for up to 90% of lung cancer cases, and continued consumption is projected to increase global cancer incidence, particularly in developing nations such as China, Russia, and India. Second-hand smoke among children and spouses has likewise been implicated. Radon from natural underground uranium decay is the second leading cause of lung cancer in the developed world. Occupational hazards such as asbestos and environmental exposures such as air pollution, arsenic, and HIV and Tb infection have all been implicated in lung carcinogenesis, while cannabis smoking, electronic cigarettes, heated tobacco products, and COVID-19 have been hypothesized to increase risk.

OBJECTIVE: Neutrophils are an important component of the inflammatory response that characterizes acute lung injury (ALI). This discussion aims to review the contribution of neutrophils to the development and progression of ALI and to highlight the major intracellular signaling pathways that are involved in neutrophil activation in the setting of ALI. DATA SOURCES: MEDLINE, original research papers, and review papers. STUDY SELECTION: Relevant laboratory and clinical studies. DATA EXTRACTION: Systemic review. DATA SYNTHESIS: Activated neutrophils appear to play a central role in the development of most cases of ALI. In experimental models, the elimination of neutrophils markedly decreases the severity of ALI. Furthermore, in neutropenic patients with lung injury, deterioration of pulmonary function as neutropenia resolves has been well described. The neutrophils that accumulate in the lungs in models of ALI demonstrate increased activation of the kinases Akt and p38; increased nuclear accumulation of the transcriptional regulatory factor, nuclear factor-kappaB; and increased production of proinflammatory cytokines, particularly those whose transcription is dependent on nuclear factor-kappaB. Decreased apoptosis among neutrophils in the lungs is also characteristic. Inhibiting p38, Akt, or nuclear factor-kappaB activation diminishes the severity of endotoxin- or hemorrhage-induced ALI. CONCLUSIONS: The accumulation of activated neutrophils in the lungs is an early step in the pulmonary inflammatory process that leads to ALI. Although experimental models indicate that the activation of p38, Akt, and nuclear factor-kappaB in neutrophils contributes to ALI, the relative importance of these pathways in critically ill patients remains to be determined. Nevertheless, modulation of the activation of p38, Akt, and nuclear factor-kappaB in neutrophils appears to be an appropriate therapeutic target in severely ill patients with ALI.

OBJECTIVE: We developed a digital image database (www.macnet.or.jp/jsrt2/cdrom_nodules.html ) of 247 chest radiographs with and without a lung nodule. The aim of this study was to investigate the characteristics of image databases for potential use in various digital image research projects. Radiologists' detection of solitary pulmonary nodules included in the database was evaluated using a receiver operating characteristic (ROC) analysis. MATERIALS AND METHODS: One hundred and fifty-four conventional chest radiographs with a lung nodule and 93 radiographs without a nodule were selected from 14 medical centers and were digitized by a laser digitizer with a 2048 x 2048 matrix size (0.175-mm pixels) and a 12-bit gray scale. Lung nodule images were classified into five groups according to the degrees of subtlety shown. The observations of 20 participating radiologists were subjected to ROC analysis for detecting solitary pulmonary nodules. Experimental results (areas under the curve, Az) obtained from observer studies were used for characterization of five groups of lung nodules with different degrees of subtlety. RESULTS: ROC analysis showed that the database included a wide range of various nodules yielding Az values from 0.574 to 0.991 for the five categories of cases for different degrees of subtlety. CONCLUSION: This database can be useful for many purposes, including research, education, quality assurance, and other demonstrations.