ABL kinase inhibition promotes lung regeneration through expansion of an SCGB1A1+ SPC+ cell population following bacterial pneumonia

Current therapeutic interventions for the treatment of respiratory infections are hampered by the evolution of multidrug resistance in pathogens as well as the lack of effective cellular targets. Despite the identification of multiple region-specific lung progenitor cells, the identity of molecules that might be therapeutically targeted in response to infections to promote activation of progenitor cell types remains elusive. Here, we report that loss of Abl1 specifically in SCGB1A1-expressing cells leads to a significant increase in the proliferation and differentiation of bronchiolar epithelial cells, resulting in dramatic expansion of an SCGB1A1+ airway cell population that coexpresses SPC, a marker for type II alveolar cells that promotes alveolar regeneration following bacterial pneumonia. Furthermore, treatment with an Abl-specific allosteric inhibitor enhanced regeneration of the alveolar epithelium and promoted accelerated recovery of mice following pneumonia. These data reveal a potential actionable target that may be exploited for efficient recovery after pathogen-induced infections.

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FINE STRUCTURAL IDENTIFICATION OF PEROXISOMES IN MOUSE AND RAT BRONCHIOLAR AND ALVEOLAR EPITHELIUM

Journal of Histochemistry & Cytochemistry ◽

10.1177/19.6.339 ◽

1971 ◽

Vol 19 (6) ◽

pp. 339-348 ◽

Cited By ~ 47

Author(s):

PETR PETRIK

Keyword(s):

Alveolar Epithelium ◽

Average Diameter ◽

Cell Types ◽

Type Ii ◽

Clara Cells ◽

Alveolar Cells ◽

Secretion Granules ◽

Type Ii Alveolar Cells ◽

The One ◽

Average Size

Following incubation in Novikoff and Goldfischer's alkaline modification of Graham and Karnovsky's diaminobenzidine (DAB) medium, densely stained bodies were identified in the bronchiolar nonciliated cells (Clara cells) and in type II alveolar cells (great alveolar cells, granular pneumonocytes) in mouse and rat lung. In Clara cells, the electron-dense reaction product was distributed in spherical, single membrane-bound bodies having an average diameter of 0.3-0.4 µ but varying from 0.15-0.65 µ. Neither nucleoids nor crystalline cores were seen inside these structures. These bodies were seen to be often closely associated with rough endoplasmic reticulum cisternae. The electron-lucent vesicles, some of them with a dense core, previously reported as secretion granules, never stained with DAB. The DAB-stained bodies present in type II alveolar cells had a somewhat different morphology. They were often elongated, with an average size of 0.2-0.3 x 0.1 µ but varying between 0.6 and 0.08 µ. The electron density of their staining was the same as in the DAB-positive bodies of Clara cells. Both cell types were studied for acid phosphatase activity; the distribution pattern of the reaction was entirely different from the one reported above. Considering the specificity of this modified reaction and the effect of inhibitors, it is assumed that the DAB-stained bodies present in both Clara and type II alveolar cells—in spite of a slightly atypical aspect in the latter—are peroxisomes.

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GM-CSF: Orchestrating the Pulmonary Response to Infection

Frontiers in Pharmacology ◽

10.3389/fphar.2021.735443 ◽

2022 ◽

Vol 12 ◽

Author(s):

Thomas S. McCormick ◽

Rana B. Hejal ◽

Luis O. Leal ◽

Mahmoud A. Ghannoum

Keyword(s):

Infectious Diseases ◽

Respiratory Infections ◽

Critical Role ◽

Alveolar Epithelium ◽

Cell Types ◽

Adjunctive Treatment ◽

Gm Csf ◽

Lung Physiology ◽

Pulmonary Immune System ◽

And Function

This review summarizes the structure and function of the alveolar unit, comprised of alveolar macrophage and epithelial cell types that work in tandem to respond to infection. Granulocyte-macrophage colony-stimulating factor (GM-CSF) helps to maintain the alveolar epithelium and pulmonary immune system under physiological conditions and plays a critical role in restoring homeostasis under pathologic conditions, including infection. Given the emergence of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and global spread of coronavirus disease 2019 (COVID-19), with subsequent acute respiratory distress syndrome, understanding basic lung physiology in infectious diseases is especially warranted. This review summarizes clinical and preclinical data for GM-CSF in respiratory infections, and the rationale for sargramostim (yeast-derived recombinant human [rhu] GM-CSF) as adjunctive treatment for COVID-19 and other pulmonary infectious diseases.

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Ectopeptidases of alveolar epithelium: candidates for roles in alveolar regulatory mechanisms

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1991.260.6.l381 ◽

1991 ◽

Vol 260 (6) ◽

pp. L381-L385

Author(s):

J. D. Funkhouser ◽

S. D. Tangada ◽

R. D. Peterson

Keyword(s):

Biological Activity ◽

Epithelial Cells ◽

Alveolar Epithelium ◽

Cell Types ◽

Alveolar Epithelial Cells ◽

Regulatory Mechanisms ◽

Luminal Surface ◽

Biological Feature ◽

Alveolar Cells ◽

Alveolar Epithelial

This commentary discusses the implications of recent observations indicating that at least one, and probably three, ectopeptidases are exhibited on the surface of alveolar epithelial cells. The unique biological feature of the ectopeptidases is that they are expressed on the surface of only selected cell types and at specific stages in the differentiation of those cells. Consequently they are positioned to exert their enzymatic activity in a very restricted locale. Drawing from information derived from studies of this activity on other cells, we develop the proposition that the ectopeptidases on alveolar epithelial cells regulate the biological activity of peptides encountered at this site. These may be peptides produced by the alveolar epithelial cells or cytokines that have the potential of influencing the alveolar cells. Awareness that these ectopeptidases are expressed on the luminal surface of these cells thus opens heretofore unrecognized avenues of investigation.

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Single cell transcriptomic analysis of murine lung development on hyperoxia-induced damage

Nature Communications ◽

10.1038/s41467-021-21865-2 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Maria Hurskainen ◽

Ivana Mižíková ◽

David P. Cook ◽

Noora Andersson ◽

Chanèle Cyr-Depauw ◽

...

Keyword(s):

Single Cell ◽

Lung Development ◽

Alveolar Epithelium ◽

Cell Types ◽

Capillary Endothelium ◽

Stromal Fibroblasts ◽

Main Driver ◽

Macrophage Populations ◽

Induced Changes ◽

Cellular Compartments

AbstractDuring late lung development, alveolar and microvascular development is finalized to enable sufficient gas exchange. Impaired late lung development manifests as bronchopulmonary dysplasia (BPD) in preterm infants. Single-cell RNA sequencing (scRNA-seq) allows for assessment of complex cellular dynamics during biological processes, such as development. Here, we use MULTI-seq to generate scRNA-seq profiles of over 66,000 cells from 36 mice during normal or impaired lung development secondary to hyperoxia with validation of some of the findings in lungs from BPD patients. We observe dynamic populations of cells, including several rare cell types and putative progenitors. Hyperoxia exposure, which mimics the BPD phenotype, alters the composition of all cellular compartments, particularly alveolar epithelium, stromal fibroblasts, capillary endothelium and macrophage populations. Pathway analysis and predicted dynamic cellular crosstalk suggest inflammatory signaling as the main driver of hyperoxia-induced changes. Our data provides a single-cell view of cellular changes associated with late lung development in health and disease.

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Diving into the Pleural Fluid: Liquid Biopsy for Metastatic Malignant Pleural Effusions

Cancers ◽

10.3390/cancers13112798 ◽

2021 ◽

Vol 13 (11) ◽

pp. 2798

Author(s):

Maria Alba Sorolla ◽

Anabel Sorolla ◽

Eva Parisi ◽

Antonieta Salud ◽

José M. Porcel

Keyword(s):

Pleural Fluid ◽

Liquid Biopsy ◽

Cell Types ◽

Circulating Tumor Dna ◽

Therapeutic Interventions ◽

Driver Mutations ◽

Pleural Effusions ◽

Malignant Pleural Effusions ◽

Micro Rnas ◽

Low Sensitivity

Liquid biopsy is emerging as a promising non-invasive diagnostic tool for malignant pleural effusions (MPE) due to the low sensitivity of conventional pleural fluid (PF) cytological examination and the difficulty to obtain tissue biopsies, which are invasive and require procedural skills. Currently, liquid biopsy is increasingly being used for the detection of driver mutations in circulating tumor DNA (ctDNA) from plasma specimens to guide therapeutic interventions. Notably, malignant PF are richer than plasma in tumor-derived products with potential clinical usefulness, such as ctDNA, micro RNAs (miRNAs) and long non-coding RNAs (lncRNAs), and circulating tumor cells (CTC). Tumor-educated cell types, such as platelets and macrophages, have also been added to this diagnostic armamentarium. Herein, we will present an overview of the role of the preceding biomarkers, collectively known as liquid biopsy, in PF samples, as well as the main technical approaches used for their detection and quantitation, including a proper sample processing. Technical limitations of current platforms and future perspectives in the field will also be addressed. Using PF as liquid biopsy shows promise for use in current practice to facilitate the diagnosis and management of metastatic MPE.

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Molecular Alterations in Sporadic and SOD1-ALS Immortalized Lymphocytes: Towards a Personalized Therapy

International Journal of Molecular Sciences ◽

10.3390/ijms22063007 ◽

2021 ◽

Vol 22 (6) ◽

pp. 3007

Author(s):

Isabel Lastres-Becker ◽

Gracia Porras ◽

Marina Arribas-Blázquez ◽

Inés Maestro ◽

Daniel Borrego-Hernández ◽

...

Keyword(s):

Motor Neurons ◽

Molecular Mechanisms ◽

Cell Types ◽

Therapeutic Interventions ◽

Autophagic Flux ◽

Metabolic Disturbances ◽

Molecular Alterations ◽

Healthy Donors ◽

Inflammatory Profile ◽

Als Patients

Amyotrophic lateral sclerosis (ALS) is a fatal neurological condition where motor neurons (MNs) degenerate. Most of the ALS cases are sporadic (sALS), whereas 10% are hereditarily transmitted (fALS), among which mutations are found in the gene that codes for the enzyme superoxide dismutase 1 (SOD1). A central question in ALS field is whether causative mutations display selective alterations not found in sALS patients, or they converge on shared molecular pathways. To identify specific and common mechanisms for designing appropriate therapeutic interventions, we focused on the SOD1-mutated (SOD1-ALS) versus sALS patients. Since ALS pathology involves different cell types other than MNs, we generated lymphoblastoid cell lines (LCLs) from sALS and SOD1-ALS patients and healthy donors and investigated whether they show changes in oxidative stress, mitochondrial dysfunction, metabolic disturbances, the antioxidant NRF2 pathway, inflammatory profile, and autophagic flux. Both oxidative phosphorylation and glycolysis appear to be upregulated in lymphoblasts from sALS and SOD1-ALS. Our results indicate significant differences in NRF2/ARE pathway between sALS and SOD1-ALS lymphoblasts. Furthermore, levels of inflammatory cytokines and autophagic flux discriminate between sALS and SOD1-ALS lymphoblasts. Overall, different molecular mechanisms are involved in sALS and SOD1-ALS patients and thus, personalized medicine should be developed for each case.

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The neural crest population responding to endothelin-3 in vitro includes multipotent cells

Journal of Cell Science ◽

10.1242/jcs.110.14.1673 ◽

1997 ◽

Vol 110 (14) ◽

pp. 1673-1682 ◽

Cited By ~ 1

Author(s):

J.G. Stone ◽

L.I. Spirling ◽

M.K. Richardson

Keyword(s):

Neural Crest ◽

Schwann Cells ◽

Cell Types ◽

Developmental Potential ◽

Colony Assay ◽

Cellular Targets ◽

Multipotent Cells ◽

Endothelin 3

The peptide endothelin 3 (EDN3) is essential for normal neural crest development in vivo, and is a potent mitogen for quail truncal crest cells in vitro. It is not known which subpopulations of crest cells are targets for this response, although it has been suggested that EDN3 is selective for melanoblasts. In the absence of cell markers for different precursor types in the quail crest, we have characterised EDN3-responsive cell types using in vitro colony assay and clonal analysis. Colonies were analysed for the presence of Schwann cells, melanocytes, adrenergic cells or sensory-like cells. We provide for the first time a description of the temporal pattern of lineage segregation in neural crest cultures. In the absence of exogenous EDN3, crest cells proliferate and then differentiate. Colony assay indicates that in these differentiated cultures few undifferentiated precursors remain and there is a low replating efficiency. By contrast, in the presence of 100 ng/ml EDN3 differentiation is inhibited and most of the cells maintain the ability to give rise to mixed colonies and clones containing neural crest derivatives. A high replating efficiency is maintained. In secondary culture there was a progressive decline in the number of cell types per colony in control medium. This loss of developmental potential was not seen when exogenous EDN3 was present. Cell type analysis suggests two novel cellular targets for EDN3 under these conditions. Contrary to expectations, one is a multipotent precursor whose descendants include melanocytes, adrenergic cells and sensory-like cells; the other can give rise to melanocytes and Schwann cells. Our data do not support previous claims that the action of EDN3 in neural crest culture is selective for cells in the melanocyte lineage.

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Nuclear receptor Nur77: its role in chronic inflammatory diseases

Essays in Biochemistry ◽

10.1042/ebc20210004 ◽

2021 ◽

Author(s):

Sanne C. Lith ◽

Carlie J.M. de Vries

Keyword(s):

Nuclear Receptor ◽

Inflammatory Disease ◽

Inflammatory Responses ◽

Current Knowledge ◽

Inflammatory Diseases ◽

Cell Types ◽

Experimental Models ◽

Therapeutic Interventions ◽

Alternative Mechanism ◽

Signaling Complex

Abstract Nur77 is a nuclear receptor that has been implicated as a regulator of inflammatory disease. The expression of Nur77 increases upon stimulation of immune cells and is differentially expressed in chronically inflamed organs in human and experimental models. Furthermore, in a variety of animal models dedicated to study inflammatory diseases, changes in Nur77 expression alter disease outcome. The available studies comprise a wealth of information on the function of Nur77 in diverse cell types and tissues. Negative cross-talk of Nur77 with the NFκB signaling complex is an example of Nur77 effector function. An alternative mechanism of action has been established, involving Nur77-mediated modulation of metabolism in macrophages as well as in T cells. In this review, we summarize our current knowledge on the role of Nur77 in atherosclerosis, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, and sepsis. Detailed insight in the control of inflammatory responses will be essential in order to advance Nur77-targeted therapeutic interventions in inflammatory disease.

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Mesenchymal Stem Cells and Cancer Stem Cells: An Overview of Tumor-Mesenchymal Stem Cell Interaction for therapeutic interventions

Current Drug Targets ◽

10.2174/1389450122666210824142247 ◽

2021 ◽

Vol 22 ◽

Author(s):

Soheila Montazersaheb ◽

Ezzatollah Fathi ◽

Ayoub Mamandi ◽

Raheleh Farahzadi ◽

Hamid Reza Heidari

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Tumor Microenvironment ◽

Cancer Stem Cells ◽

Tumor Cells ◽

Cell Types ◽

Cell Interaction ◽

Therapeutic Interventions ◽

Tumorigenic Potential ◽

Different Types

: Tumors are made up of different types of cancer cells that contribute to tumor heterogeneity. Among these cells, cancer stem cells (CSCs) have a significant role in the onset of cancer and development. Like other stem cells, CSCs are characterized by the capacity for differentiation and self-renewal. A specific population of CSCs is constituted by mesenchymal stem cells (MSCs) that differentiate into mesoderm-specific cells. The pro-or anti-tumorigenic potential of MSCs on the proliferation and development of tumor cells has been reported as contradictory results. Also, tumor progression is specified by the corresponding tumor cells like the tumor microenvironment. The tumor microenvironment consists of a network of reciprocal cell types such as endothelial cells, immune cells, MSCs, and fibroblasts as well as growth factors, chemokines, and cytokines. In this review, recent findings related to the tumor microenvironment and associated cell populations, homing of MSCs to tumor sites, and interaction of MSCs with tumor cells will be discussed.

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