New Pharmacological Tools to Target Leukocyte Trafficking in Lung Disease

Infection and inflammation of the lung results in the recruitment of non-resident immune cells, including neutrophils, eosinophils and monocytes. This swift response should ensure clearance of the threat and resolution of stimuli which drive inflammation. However, once the threat is subdued this influx of immune cells should be followed by clearance of recruited cells through apoptosis and subsequent efferocytosis, expectoration or retrograde migration back into the circulation. This cycle of cell recruitment, containment of threat and then clearance of immune cells and repair is held in exquisite balance to limit host damage. Advanced age is often associated with detrimental changes to the balance described above. Cellular functions are altered including a reduced ability to traffic accurately towards inflammation, a reduced ability to clear pathogens and sustained inflammation. These changes, seen with age, are heightened in lung disease, and most chronic and acute lung diseases are associated with an exaggerated influx of immune cells, such as neutrophils, to the airways as well as considerable inflammation. Indeed, across many lung diseases, pathogenesis and progression has been associated with the sustained presence of trafficking cells, with examples including chronic diseases such as Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis and acute infections such as Pneumonia and Pneumonitis. In these instances, there is evidence that dysfunctional and sustained recruitment of cells to the airways not only increases host damage but impairs the hosts ability to effectively respond to microbial invasion. Targeting leukocyte migration in these instances, to normalise cellular responses, has therapeutic promise. In this review we discuss the current evidence to support the trafficking cell as an immunotherapeutic target in lung disease, and which potential mechanisms or pathways have shown promise in early drug trials, with a focus on the neutrophil, as the quintessential trafficking immune cell.

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Pulmonary Evaluation

Mayo Clinic Internal Medicine Board Review ◽

10.1093/med/9780190464868.003.0074 ◽

2016 ◽

pp. 747-766

Author(s):

Vivek N. Iyer

Keyword(s):

Chronic Obstructive Pulmonary Disease ◽

Cystic Fibrosis ◽

Lung Disease ◽

Lung Diseases ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease ◽

Airway Stenosis ◽

Obstructive Lung Diseases ◽

Diffuse Panbronchiolitis ◽

Antitrypsin Deficiency

Obstructive lung diseases include chronic obstructive pulmonary disease (COPD) (eg, chronic bronchitis and emphysema), asthma, bronchiectasis, cystic fibrosis, obliterative bronchiolitis, and diffuse panbronchiolitis (eg, bullous lung disease, α‎1-antitrypsin deficiency, and airway stenosis). The 2 most prevalent obstructive lung diseases are COPD and asthma.

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COVID-19 and restrictive lung disease: A deadly combo to trip off the fine balance

Monaldi Archives for Chest Disease ◽

10.4081/monaldi.2020.1346 ◽

2020 ◽

Vol 90 (2) ◽

Cited By ~ 2

Author(s):

Kamal Kant Sahu ◽

Ajay Kumar Mishra ◽

Kevin Martin ◽

Iryna Chastain

Keyword(s):

Risk Factors ◽

Chronic Obstructive Pulmonary Disease ◽

Risk Factor ◽

Lung Disease ◽

Lung Diseases ◽

Chronic Obstructive ◽

Immunocompromised Patients ◽

Obstructive Pulmonary Disease ◽

Restrictive Lung Disease ◽

Chronic Lung Diseases

Coronavirus Disease (COVID-19) pandemic has so far led to innumerable deaths worldwide. The risk factors so far that have been most studied as poor prognostic factors are old age, individuals with multiple comorbidities and immunocompromised patients. Amongst the chronic lung diseases, most patients with COVID-19 reported so far had asthma, chronic obstructive pulmonary disease (COPD), and interstitial lung disease. Herein, we discuss the significance of restrictive lung disease during the COVID-19 pandemic as a potential risk factor via an example of a patient with kyphoscoliosis who succumbed to death due to COVID-19 pneumonia.

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Chemokine receptors and their therapeutic opportunities in diseased lung: Far beyond leukocyte trafficking

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00203.2014 ◽

2015 ◽

Vol 308 (7) ◽

pp. L603-L618 ◽

Cited By ~ 24

Author(s):

Tereza Tomankova ◽

Eva Kriegova ◽

Mingyao Liu

Keyword(s):

Lung Tissue ◽

Chemokine Receptors ◽

Lung Diseases ◽

Immune Cell ◽

Critical Role ◽

Chronic Obstructive ◽

Potential Contribution ◽

Cell Trafficking ◽

Obstructive Pulmonary Disease ◽

Current State

Chemokine receptors and their chemokine ligands, key mediators of inflammatory and immune cell trafficking, are involved in the regulation of both physiological and pathological processes in the lung. The discovery that chemokine receptors/chemokines, typically expressed by inflammatory and immune cells, are also expressed in structural lung tissue cells suggests their role in mediating the restoration of lung tissue structure and functions. Thus, chemokine receptors/chemokines contribute not only to inflammatory and immune responses in the lung but also play a critical role in the regulation of lung tissue repair, regeneration, and remodeling. This review aims to summarize current state-of-the-art on chemokine receptors and their ligands in lung diseases such as chronic obstructive pulmonary disease, asthma/allergy, pulmonary fibrosis, acute lung injury, and lung infection. Furthermore, the therapeutic opportunities of chemokine receptors in aforementioned lung diseases are discussed. The review also aims to delineate the potential contribution of chemokine receptors to the processes leading to repair/regeneration of the lung tissue.

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Genetically manipulated mouse models of lung disease: potential and pitfalls

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00085.2011 ◽

2012 ◽

Vol 302 (6) ◽

pp. L485-L497 ◽

Cited By ~ 41

Author(s):

Rebecca M. Baron ◽

Alexander J. S. Choi ◽

Caroline A. Owen ◽

Augustine M. K. Choi

Keyword(s):

Lung Disease ◽

Lung Diseases ◽

Genetically Engineered ◽

Chronic Obstructive ◽

Biological Processes ◽

Obstructive Pulmonary Disease ◽

Molecular Events ◽

Genetically Engineered Mice ◽

Genetically Manipulated ◽

Parenchymal Lung

Gene targeting in mice (transgenic and knockout) has provided investigators with an unparalleled armamentarium in recent decades to dissect the cellular and molecular basis of critical pathophysiological states. Fruitful information has been derived from studies using these genetically engineered mice with significant impact on our understanding, not only of specific biological processes spanning cell proliferation to cell death, but also of critical molecular events involved in the pathogenesis of human disease. This review will focus on the use of gene-targeted mice to study various models of lung disease including airways diseases such as asthma and chronic obstructive pulmonary disease, and parenchymal lung diseases including idiopathic pulmonary fibrosis, pulmonary hypertension, pneumonia, and acute lung injury. We will attempt to review the current technological approaches of generating gene-targeted mice and the enormous dataset derived from these studies, providing a template for lung investigators.

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The Role of Connexin 43 in Lung Disease

Life ◽

10.3390/life10120363 ◽

2020 ◽

Vol 10 (12) ◽

pp. 363

Author(s):

Julie A. Swartzendruber ◽

Bruce J. Nicholson ◽

Ashlesh K. Murthy

Keyword(s):

Lung Disease ◽

Lung Diseases ◽

Connexin 43 ◽

Distress Syndrome ◽

Cell Types ◽

Mortality Rates ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease ◽

Junction Proteins

The term lung disease describes a broad category of disorders that impair lung function. More than 35 million Americans have a preventable chronic lung disease with high mortality rates due to limited treatment efficacy. The recent increase in patients with lung disease highlights the need to increase our understanding of mechanisms driving lung inflammation. Connexins, gap junction proteins, and more specifically connexin 43 (Cx43), are abundantly expressed in the lung and are known to play a role in lung diseases. This review focuses on the role of Cx43 in pathology associated with acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD) and asthma. Additionally, we discuss the role of Cx43 in preventing disease through the transfer of mitochondria between cells. We aim to highlight the need to better understand what cell types are expressing Cx43 and how this expression influences lung disease.

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Macrophages with reduced expressions of classical M1 and M2 surface markers in human bronchoalveolar lavage fluid exhibit pro-inflammatory gene signatures

Scientific Reports ◽

10.1038/s41598-021-87720-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Hiroto Takiguchi ◽

Chen X. Yang ◽

Cheng Wei Tony Yang ◽

Basak Sahin ◽

Beth A. Whalen ◽

...

Keyword(s):

Bronchoalveolar Lavage ◽

Lung Diseases ◽

Inflammatory Responses ◽

Lavage Fluid ◽

Gene Signature ◽

Chronic Obstructive ◽

Surface Markers ◽

Cellular Functions ◽

Obstructive Pulmonary Disease ◽

Copd Patients

AbstractThe classical M1/M2 polarity of macrophages may not be applicable to inflammatory lung diseases including chronic obstructive pulmonary disease (COPD) due to the complex microenvironment in lungs and the plasticity of macrophages. We examined macrophage sub-phenotypes in bronchoalveolar lavage (BAL) fluid in 25 participants with CD40 (a M1 marker) and CD163 (a M2 marker). Of these, we performed RNA-sequencing on each subtype in 10 patients using the Illumina NextSeq 500. Approximately 25% of the macrophages did not harbor classical M1 or M2 surface markers (double negative, DN), and these cells were significantly enriched in COPD patients compared with non-COPD patients (46.7% vs. 14.5%, p < 0.001). 1886 genes were differentially expressed in the DN subtype compared with all other subtypes at a 10% false discovery rate. The 602 up-regulated genes included 15 mitochondrial genes and were enriched in 86 gene ontology (GO) biological processes including inflammatory responses. Modules associated with cellular functions including oxidative phosphorylation were significantly down-regulated in the DN subtype. Macrophages in the human BAL fluid, which were negative for both M1/M2 surface markers, harbored a gene signature that was pro-inflammatory and suggested dysfunction in cellular homeostasis. These macrophages may contribute to the pathogenesis and manifestations of inflammatory lung diseases such as COPD.

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Comparison of SpO2 and heart rate values on Apple Watch and conventional commercial oximeters devices in patients with lung disease

Scientific Reports ◽

10.1038/s41598-021-98453-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Leonardo Zumerkorn Pipek ◽

Rafaela Farias Vidigal Nascimento ◽

Milena Marques Pagliarelli Acencio ◽

Lisete Ribeiro Teixeira

Keyword(s):

Heart Rate ◽

Lung Disease ◽

Skin Color ◽

Lung Diseases ◽

Chronic Obstructive ◽

Negative Effects ◽

Obstructive Pulmonary Disease ◽

Mortality And Morbidity ◽

Positive Correlations ◽

Pulse Oximeters

AbstractLung diseases have high mortality and morbidity, with an important impact on quality of life. Hypoxemic patients are advised to use oxygen therapy to prolong their survival, but high oxygen saturation (SpO2) levels can also have negative effects. Pulse oximeters are the most common way to assess oxygen levels and guide medical treatment. This study aims to assess whether wearable devices can provide precise SpO2 measurements when compared to commercial pulse oximeters. This is a cross-section study with 100 patients with chronic obstructive pulmonary disease and interstitial lung disease from an outpatient pneumology clinic. SpO2 and heart rate data were collected with an Apple Watch Series 6 (Apple) and compared to two commercial pulse oximeters. The Bland–Altman method and interclass correlation coefficient were used to compare their values. We observed strong positive correlations between the Apple Watch device and commercial oximeters when evaluating heart rate measurements (r = 0.995, p < 0.001) and oximetry measurements (r = 0.81, p < 0.001). There was no statistical difference in the evaluation of skin color, wrist circumference, presence of wrist hair, and enamel nail for SpO2 and heart rate measurements in Apple Watch or commercial oximeter devices (p > 0.05). Apple Watch 6 is a reliable way to obtain heart rate and SpO2 in patients with lung diseases in a controlled environment.

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Proteases, Mucus, and Mucosal Immunity in Chronic Lung Disease

International Journal of Molecular Sciences ◽

10.3390/ijms22095018 ◽

2021 ◽

Vol 22 (9) ◽

pp. 5018

Author(s):

Michael C. McKelvey ◽

Ryan Brown ◽

Sinéad Ryan ◽

Marcus A. Mall ◽

Sinéad Weldon ◽

...

Keyword(s):

Cystic Fibrosis ◽

Lung Disease ◽

Lung Diseases ◽

Lung Damage ◽

Chronic Obstructive ◽

Lung Function Decline ◽

Obstructive Pulmonary Disease ◽

Chronic Lung Diseases ◽

Multifunctional Enzymes ◽

Disease Experience

Dysregulated protease activity has long been implicated in the pathogenesis of chronic lung diseases and especially in conditions that display mucus obstruction, such as chronic obstructive pulmonary disease, cystic fibrosis, and non-cystic fibrosis bronchiectasis. However, our appreciation of the roles of proteases in various aspects of such diseases continues to grow. Patients with muco-obstructive lung disease experience progressive spirals of inflammation, mucostasis, airway infection and lung function decline. Some therapies exist for the treatment of these symptoms, but they are unable to halt disease progression and patients may benefit from novel adjunct therapies. In this review, we highlight how proteases act as multifunctional enzymes that are vital for normal airway homeostasis but, when their activity becomes immoderate, also directly contribute to airway dysfunction, and impair the processes that could resolve disease. We focus on how proteases regulate the state of mucus at the airway surface, impair mucociliary clearance and ultimately, promote mucostasis. We discuss how, in parallel, proteases are able to promote an inflammatory environment in the airways by mediating proinflammatory signalling, compromising host defence mechanisms and perpetuating their own proteolytic activity causing structural lung damage. Finally, we discuss some possible reasons for the clinical inefficacy of protease inhibitors to date and propose that, especially in a combination therapy approach, proteases represent attractive therapeutic targets for muco-obstructive lung diseases.

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Occupational and Environmental Lung Diseases: Diagnosis and Prevention

10.2310/fm.1204 ◽

2017 ◽

Author(s):

Cora S Sack ◽

Sverre Vedal ◽

Joel D Kaufman

Keyword(s):

Chronic Obstructive Pulmonary Disease ◽

Lung Disease ◽

Pulmonary Disease ◽

Occupational Asthma ◽

Lung Diseases ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease ◽

Occupational Lung Disease ◽

Work Related ◽

Occupational Lung Diseases

Environmental and occupational lung diseases encompass a diverse group of lung diseases caused by the inhalation of potentially harmful substances. Although workplace regulations and the changing economy in the United States have significantly decreased incidence, these diseases remain both common and associated with significant morbidity. In addition, novel exposures continue to be recognized as new causes of disease. This review provides the medical student and clinician with a framework for approaching and categorizing environmental and occupational lung disease. It also presents an in-depth discussion of the epidemiology, biological mechanisms, diagnosis, and clinical care of some of the more commonly encountered diseases. Occupational lung diseases that affect the airways, such as work-related asthma and chronic obstructive pulmonary disease, and malignant neoplasms are covered. This review concludes with general strategies to help prevent disease incidence and progression. This review contains 1 figure, 5 tables, and 56 references. Key words: bronchiolitis obliterans, chronic obstructive pulmonary disease, irritant-induced occupational asthma, mesothelioma, occupational asthma, occupational lung disease, occupational lung neoplasm, work-related asthma

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