RESEARCH OF EXPRESSION MECHANISM OF SLC34A2 GENE AT PAM ALVEOLAR EPITHELIUM

Dogs were injected intravenously with E_. coli endotoxin (2 mg/kg), and lung samples were taken at 15 min., 1 hr. and 24 hrs. At 15 min., occlusion of pulmonary capillaries by degranulating platelets and polymorphonuclear leukocytes (PML) was evident (Fig. 1). Capillary endothelium was intact but endothelial damage in small arteries and arterioles, accompanied by intraalveolar hemorrhage, was frequent (Fig. 2). Sloughing of the surfactant layer from alveolar epithelium was evident (Fig. 1). At 1 hr., platelet-PML plugs were no longer seen in capillaries, the endothelium of which was often vacuolated (Fig. 3). Interstitial edema and destruction of alveolar epithelium were seen, and type II cells had discharged their granules into the alveoli (Fig. 4). At 24 hr. phagocytic PML's were frequent in peripheral alveoli, while centrally, alveoli and vessels were packed with fibrin thrombi and PML's (Fig. 5). In similar dogs rendered thrombocytopenic with anti-platelet serum, lung ultrastructure was similar to that of controls, although PML's were more frequently seen in capillaries in the former (Fig. 6).

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The effect of bromocriptine on mammary-gland ultrastructure of hyperprolactinemic rats

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100111136 ◽

1984 ◽

Vol 42 ◽

pp. 204-205

Author(s):

I.C. Murray

Keyword(s):

Mammary Gland ◽

Dopamine Agonist ◽

Alveolar Epithelium ◽

Mammary Glands ◽

Female Rats ◽

Control Group ◽

Cell Hyperplasia ◽

Once Daily ◽

Long Evans

In women, hyperprolactinemia is often due to a prolactin (PRL)-secreting adenoma or PRL cell hyperplasia. RRL excess stimulates the mammary glands and causes proliferation of the alveolar epithelium. Bromocriptine, a dopamine agonist, inhibits PRL secretion and is given to women to treat nonpuerperal galactorrhea. Old female rats have been reported to have PRL cell hyperplasia or adenoma leading to PRL hypersecretion and breast stimulation. Herein, we describe the effect of bromocriptine and consequently the reduction in serum PRL levels on the ultrastructure of rat mammary glands.Female Long-Evans rats, 23 months of age, were divided into control and bromocriptine-treated groups. The control animals were injected subcutaneously once daily with a 10% ethanol vehicle and were later divided into a normoprolactinemic control group with serum PRL levels under 30 ng/ml and a hyperprolactinemic control group with serum PRL levels above 30 ng/ml.

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Faculty Opinions recommendation of Sterol regulatory element-binding protein-2- and liver X receptor-driven dual promoter regulation of hepatic ABC transporter A1 gene expression: mechanism underlying the unique response to cellular cholesterol status.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1090217.543438 ◽

2007 ◽

Author(s):

Axel Nohturfft

Keyword(s):

Gene Expression ◽

Abc Transporter ◽

Regulatory Element ◽

Liver X Receptor ◽

Promoter Regulation ◽

Cellular Cholesterol ◽

Element Binding Protein ◽

Sterol Regulatory Element ◽

Cholesterol Status ◽

Expression Mechanism

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Cross-species integration of single-cell RNA-seq resolved alveolar-epithelial transitional states in idiopathic pulmonary fibrosis

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00594.2020 ◽

2021 ◽

Author(s):

Kevin Y. Huang ◽

Enrico Petretto

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Single Cell ◽

Transitional Cell ◽

Notch Pathway ◽

Alveolar Epithelium ◽

State Transitions ◽

Specific Cell ◽

Differentiation Process ◽

Cell State

Single-cell transcriptomics analyses of the fibrotic lung uncovered two cell states critical to lung injury recovery in the alveolar epithelium- a reparative transitional cell state in the mouse and a disease-specific cell state (KRT5-/KRT17+) in human idiopathic pulmonary fibrosis (IPF). The murine transitional cell state lies between the differentiation from type 2 (AT2) to type 1 pneumocyte (AT1), and the human KRT5-/KRT17+ cell state may arise from the dysregulation of this differentiation process. We review major findings of single-cell transcriptomics analyses of the fibrotic lung and re-analyzed data from 7 single-cell RNA sequencing studies of human and murine models of IPF, focusing on the alveolar epithelium. Our comparative and cross-species single-cell transcriptomics analyses allowed us to further delineate the differentiation trajectories from AT2 to AT1 and AT2 to the KRT5-/KRT17+ cell state. We observed AT1 cells in human IPF retain the transcriptional signature of the murine transitional cell state. Using pseudotime analysis, we recapitulated the differentiation trajectories from AT2 to AT1 and from AT2 to KRT5-/KRT17+ cell state in multiple human IPF studies. We further delineated transcriptional programs underlying cell state transitions and determined the molecular phenotypes at terminal differentiation. We hypothesize that in addition to the reactivation of developmental programs (SOX4, SOX9), senescence (TP63, SOX4) and the Notch pathway (HES1) are predicted to steer intermediate progenitors to the KRT5-/KRT17+ cell state. Our analyses suggest that activation of SMAD3 later in the differentiation process may explain the fibrotic molecular phenotype typical of KRT5-/KRT17+ cells.

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Expression of Surfactant protein D (SP-D) distinguishes severe pandemic influenza A(H1N1) from COVID-19

The Journal of Infectious Diseases ◽

10.1093/infdis/jiab113 ◽

2021 ◽

Author(s):

José Alberto Choreño-Parra ◽

Luis Armando Jiménez-Álvarez ◽

Gustavo Ramírez-Martínez ◽

Alfredo Cruz-Lagunas ◽

Mahima Thapa ◽

...

Keyword(s):

Pandemic Influenza ◽

Influenza A ◽

Alveolar Epithelium ◽

Surfactant Protein ◽

High Serum ◽

Surfactant Protein D ◽

Diagnostic Challenge ◽

Moderate Disease ◽

Influenza A H1n1 ◽

Novel Biomarkers

Abstract The differentiation of influenza and COVID-19 could constitute a diagnostic challenge during the ongoing winter due to their clinical similitude. Thus, novel biomarkers that enable distinguishing both diseases are required. Here, we evaluated whether the surfactant protein D (SP-D), a collectin produced at the alveolar epithelium with known immune properties, was useful to differentiate pandemic influenza A(H1N1) from COVID-19 in critically ill patients. Our results revealed high serum SP-D levels in severe pandemic influenza but not COVID-19 patients. This finding was validated in a separate cohort of mechanically ventilated COVID-19 patients who also showed low plasma SP-D levels. However, plasma SP-D levels did not distinguish seasonal influenza from COVID-19 in mild-to-moderate disease. Finally, we found that high serum SP-D levels were associated with mortality and renal failure among severe pandemic influenza cases. Thus, our studies have identified SP-D as a unique biomarker expressed during severe pandemic influenza but not COVID-19.

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Pulmonary Stretch and Lung Mechanotransduction: Implications for Progression in the Fibrotic Lung

International Journal of Molecular Sciences ◽

10.3390/ijms22126443 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6443

Author(s):

Alessandro Marchioni ◽

Roberto Tonelli ◽

Stefania Cerri ◽

Ivana Castaniere ◽

Dario Andrisani ◽

...

Keyword(s):

Pulmonary Fibrosis ◽

Spontaneous Breathing ◽

Elastic Limit ◽

Physiological Stress ◽

Fibrous Tissue ◽

Ventilatory Support ◽

Biological Response ◽

Alveolar Epithelium ◽

Strain Curve ◽

Mechanical Forces

Lung fibrosis results from the synergic interplay between regenerative deficits of the alveolar epithelium and dysregulated mechanisms of repair in response to alveolar and vascular damage, which is followed by progressive fibroblast and myofibroblast proliferation and excessive deposition of the extracellular matrix. The increased parenchymal stiffness of fibrotic lungs significantly affects respiratory mechanics, making the lung more fragile and prone to non-physiological stress during spontaneous breathing and mechanical ventilation. Given their parenchymal inhomogeneity, fibrotic lungs may display an anisotropic response to mechanical stresses with different regional deformations (micro-strain). This behavior is not described by the standard stress–strain curve but follows the mechano-elastic models of “squishy balls”, where the elastic limit can be reached due to the excessive deformation of parenchymal areas with normal elasticity that are surrounded by inelastic fibrous tissue or collapsed induration areas, which tend to protrude outside the fibrous ring. Increasing evidence has shown that non-physiological mechanical forces applied to fibrotic lungs with associated abnormal mechanotransduction could favor the progression of pulmonary fibrosis. With this review, we aim to summarize the state of the art on the relation between mechanical forces acting on the lung and biological response in pulmonary fibrosis, with a focus on the progression of damage in the fibrotic lung during spontaneous breathing and assisted ventilatory support.

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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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SPAK-p38 MAPK signal pathway modulates claudin-18 and barrier function of alveolar epithelium after hyperoxic exposure

BMC Pulmonary Medicine ◽

10.1186/s12890-021-01408-7 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Chih-Hao Shen ◽

Jr-Yu Lin ◽

Cheng-Yo Lu ◽

Sung-Sen Yang ◽

Chung-Kan Peng ◽

...

Keyword(s):

P38 Mapk ◽

Knockout Mice ◽

Barrier Function ◽

Alveolar Epithelium ◽

Signal Pathway ◽

Control Group ◽

Barrier Dysfunction ◽

Hyperoxic Exposure ◽

Monolayer Permeability ◽

Mapk Signal Pathway

Abstract Background Hyperoxia downregulates the tight junction (TJ) proteins of the alveolar epithelium and leads to barrier dysfunction. Previous study has showed that STE20/SPS1-related proline/alanine-rich kinase (SPAK) interferes with the intestinal barrier function in mice. The aim of the present study is to explore the association between SPAK and barrier function in the alveolar epithelium after hyperoxic exposure. Methods Hyperoxic acute lung injury (HALI) was induced by exposing mice to > 99% oxygen for 64 h. The mice were randomly allotted into four groups comprising two control groups and two hyperoxic groups with and without SPAK knockout. Mouse alveolar MLE-12 cells were cultured in control and hyperoxic conditions with or without SPAK knockdown. Transepithelial electric resistance and transwell monolayer permeability were measured for each group. In-cell western assay was used to screen the possible mechanism of p-SPAK being induced by hyperoxia. Results Compared with the control group, SPAK knockout mice had a lower protein level in the bronchoalveolar lavage fluid in HALI, which was correlated with a lower extent of TJ disruption according to transmission electron microscopy. Hyperoxia down-regulated claudin-18 in the alveolar epithelium, which was alleviated in SPAK knockout mice. In MLE-12 cells, hyperoxia up-regulated phosphorylated-SPAK by reactive oxygen species (ROS), which was inhibited by indomethacin. Compared with the control group, SPAK knockdown MLE-12 cells had higher transepithelial electrical resistance and lower transwell monolayer permeability after hyperoxic exposure. The expression of claudin-18 was suppressed by hyperoxia, and down-regulation of SPAK restored the expression of claudin-18. The process of SPAK suppressing the expression of claudin-18 and impairing the barrier function was mediated by p38 mitogen-activated protein kinase (MAPK). Conclusions Hyperoxia up-regulates the SPAK-p38 MAPK signal pathway by ROS, which disrupts the TJ of the alveolar epithelium by suppressing the expression of claudin-18. The down-regulation of SPAK attenuates this process and protects the alveolar epithelium against the barrier dysfunction induced by hyperoxia.

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A redox microenvironment is essential for MAPK-dependent secretion of pro-inflammatory cytokines: Modulation by glutathione (GSH/GSSG) biosynthesis and equilibrium in the alveolar epithelium

Cellular Immunology ◽

10.1016/j.cellimm.2011.04.001 ◽

2011 ◽

Vol 270 (1) ◽

pp. 53-61 ◽

Cited By ~ 13

Author(s):

John J. Haddad

Keyword(s):

Inflammatory Cytokines ◽

Alveolar Epithelium ◽

Pro Inflammatory Cytokines

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Electron Microscopic Study of the Phagocytosis Process in Lung

The Journal of Cell Biology ◽

10.1083/jcb.7.2.357 ◽

1960 ◽

Vol 7 (2) ◽

pp. 357-366 ◽

Cited By ~ 103

Author(s):

H. E. Karrer

Keyword(s):

Plasma Membrane ◽

Alveolar Macrophages ◽

Alveolar Epithelium ◽

Alveolar Epithelial Cells ◽

Electron Microscopic ◽

Double Line ◽

Alveolar Epithelial ◽

Culture Cells ◽

India Ink ◽

Intracellular Vesicles

Diluted India ink was instilled into the nasal cavity of mice and the lungs of some animals were fixed with osmium tetroxide at various intervals after one instillation. The lungs of other animals were fixed after 4, 7, 9, 16, or 18 daily instillations. The India ink was found to be phagocytized almost exclusively by the free alveolar macrophages. A few particles are occasionally seen within thin portions of alveolar epithelium, within the "small" alveolar epithelial cells, or within occasional leukocytes in the lumina of alveoli. The particles are ingested by an invagination process of the plasma membrane resulting in the formation of intracellular vesicles and vacuoles. Ultimately large amounts of India ink accumulate in the cell, occupying substantial portions of the cytoplasm. The surfaces of phagocytizing macrophages show signs of intense motility. Their cytoplasm contains numerous particles, resembling Palade particles, and a large amount of rough surfaced endoplasmic reticulum. These structures are interpreted as indicative of protein synthesis. At the level of resolution achieved in this study the membranes of this reticulum appear as single dense "lines." On the other hand, the plasma membrane and the limiting membranes of vesicles and of vacuoles often exhibit the double-line structure typical of unit membranes (Robertson, 37). The inclusion bodies appear to be the product of phagocytosis. It is believed that some of them derive from the vacuoles mentioned above, and that they correspond to similar structures seen in phase contrast cinemicrographs of culture cells. Their matrix represents phagocytized material. Certain structures within this matrix are considered as secondary and some of these structures possess an ordered form probably indicative of the presence of lipid. The possible origin and the fate of alveolar macrophages are briefly discussed.

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