scholarly journals Ineffectual AEC1 differentiation from KRT8hi transitional state without fibrosis is associated with fatal COVID-19 ARDS

2021 ◽  
Author(s):  
Christopher Ting ◽  
Mohit Aspal ◽  
Neil Vaishampayan ◽  
Steven K. Huang ◽  
Fa Wang ◽  
...  
Keyword(s):  
Alveolar Epithelial Cell ◽  
Barrier Permeability ◽  
Alveolar Epithelial ◽  
Transitional State ◽  
Epithelial Regeneration ◽  
Clinical Recovery ◽  
Ventilator Dependence ◽  
Transitional Cells ◽  
Underlying Mechanisms ◽  
And Function

AbstractCOVID-19 ARDS is associated with prolonged ventilator dependence and high mortality, but the underlying mechanisms are unknown. Critical to the pathogenesis of ARDS is injury to the alveolar epithelial cell (AEC) barrier; clinical recovery requires epithelial regeneration. We previously identified a KRT8hi transitional state that regenerating AEC2s adopt during differentiation into AEC1s, the persistence of which may be pathogenic in pulmonary fibrosis. Here, we hypothesize that ineffectual differentiation of transitional cells into AEC1s without fibrosis may perpetuate barrier permeability and poor clinical outcomes in COVID-19 ARDS. To test this hypothesis, we examined postmortem lung tissue of COVID-19 ARDS patients. We observed extensive AEC1 injury, rare mature AEC2s, and abundant transitional cells. Transitional cells were cuboidal, partially spread or, rarely, flat but did not express AEC1 markers. They formed monolayers on alveolar septa denuded of AEC1s but structurally normal without fibrosis. We conclude that ineffectual AEC1 differentiation from transitional AECs may perpetuate barrier permeability and respiratory failure in COVID-19 ARDS. In contrast to fibrosis, transitional AECs may retain the capacity for physiologic AEC1 regeneration with restoration of normal alveolar architecture and function. Novel therapies to promote AEC1 differentiation from transitional cells may accelerate barrier restitution and clinical recovery in ARDS.

YAP Regulates NFI/KLF5 Transcriptional and Epigenetic Networks Directing Alveolar Epithelial Cell Differentiation

2020 ◽  
Author(s):  
Jason J. Gokey ◽  
John Snowball ◽  
Anusha Sridharan ◽  
Parvathi Sudha ◽  
Joseph A. Kitzmiller ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Epithelial Cell ◽  
Alveolar Epithelial Cell ◽  
Alveolar Epithelial ◽  
Epithelial Cell Differentiation

MiRNA, a New Treatment Strategy for Pulmonary Fibrosis

2020 ◽  
Vol 21 ◽  
Author(s):  
Yanhong Liu ◽  
Hongguang Nie ◽  
Yan Ding ◽  
Yapeng Hou ◽  
Kejun Mao ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Epithelial Mesenchymal Transition ◽  
Alveolar Epithelial Cell ◽  
The Elderly ◽  
Matrix Remodeling ◽  
Mesenchymal Transition ◽  
Delay In Diagnosis ◽  
Alveolar Epithelial ◽  
Epithelial Cell Apoptosis ◽  
New Treatment

: Pulmonary fibrosis (PF) is the most common chronic, progressive interstitial lung disease, mainly occurring in the elderly, with a median survival of 2-4 years after diagnosis. Its high mortality rate attributes to the delay in diagnosis due to its generic symptoms, and more importantly, to the lack of effective treatments. MicroRNAs (miRNAs) are a class of small non-coding RNAs that involve in many essential cellular processes, including extracellular matrix remodeling, alveolar epithelial cell apoptosis, epithelial-mesenchymal transition, etc. We summarized the dysregulated miRNAs in TGF-β signaling pathway-mediated PF in recent years with dual effects, such as anti-fibrotic let-7 family and pro-fibrotic miR-21 members. Therefore, this review will set out the latest application of miRNAs to provide a new direction for PF treatment.

scholarly journals Tumor necrosis factor-α small interfering RNA alveolar epithelial cell-targeting nanoparticles reduce lung injury in C57BL/6J mice with sepsis

2021 ◽  
Vol 49 (1) ◽  
pp. 030006052098465
Author(s):  
Like Qian ◽  
Xi Yin ◽  
Jiahao Ji ◽  
Zhengli Chen ◽  
He Fang ◽  
...  
Keyword(s):  
Tumor Necrosis Factor ◽  
Epithelial Cell ◽  
Lung Injury ◽  
Tumor Necrosis ◽  
Alveolar Epithelial Cell ◽  
Weight Ratio ◽  
B Cell Lymphoma ◽  
Alveolar Epithelial ◽  
Tnf Α ◽  
Necrosis Factor

Background The role of tumor necrosis factor (TNF)-α small interfering (si)RNA alveolar epithelial cell (AEC)-targeting nanoparticles in lung injury is unclear. Methods Sixty C57BL/6J mice with sepsis were divided into normal, control, sham, 25 mg/kg, 50 mg/kg, and 100 mg/kg siRNA AEC-targeting nanoparticles groups (n = 10 per group). The wet:dry lung weight ratio, and hematoxylin and eosin staining, western blotting, and enzyme-linked immunosorbent assays for inflammatory factors were conducted to compare differences among groups. Results The wet:dry ratio was significantly lower in control and sham groups than other groups. TNF-α siRNA AEC-targeting nanoparticles significantly reduced the number of eosinophils, with significantly lower numbers in the 50 mg/kg group than in 25 mg/kg and 100 mg/kg groups. The nanoparticles also significantly reduced the expression of TNF-α, B-cell lymphoma-2, caspase 3, interleukin (IL)-1β, and IL-6, with TNF-α expression being significantly lower in the 50 mg/kg group than in 25 mg/kg and 100 mg/kg groups. Conclusion TNF-α siRNA AEC-targeting nanoparticles appear to be effective at improving lung injury-related sepsis, and 50 mg/kg may be a preferred dose option for administration.

scholarly journals Characteristics of Passive Solute Transport across Primary Rat Alveolar Epithelial Cell Monolayers

Membranes ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 331
Author(s):  
Yong Ho Kim ◽  
Kwang-Jin Kim ◽  
David Z. D’Argenio ◽  
Edward D. Crandall
Keyword(s):  
Epithelial Cell ◽  
Tight Junctions ◽  
Pore Radius ◽  
Alveolar Epithelial Cell ◽  
Alveolar Epithelial Cells ◽  
Type I ◽  
Cell Monolayers ◽  
Alveolar Epithelial ◽  
Epithelial Cell Monolayers ◽  
Hydrophilic Solutes

Primary rat alveolar epithelial cell monolayers (RAECM) were grown without (type I cell-like phenotype, RAECM-I) or with (type II cell-like phenotype, RAECM-II) keratinocyte growth factor to assess passive transport of 11 hydrophilic solutes. We estimated apparent permeability (Papp) in the absence/presence of calcium chelator EGTA to determine the effects of perturbing tight junctions on “equivalent” pores. Papp across RAECM-I and -II in the absence of EGTA are similar and decrease as solute size increases. We modeled Papp of the hydrophilic solutes across RAECM-I/-II as taking place via heterogeneous populations of equivalent pores comprised of small (0.41/0.32 nm radius) and large (9.88/11.56 nm radius) pores, respectively. Total equivalent pore area is dominated by small equivalent pores (99.92–99.97%). The number of small and large equivalent pores in RAECM-I was 8.55 and 1.29 times greater, respectively, than those in RAECM-II. With EGTA, the large pore radius in RAECM-I/-II increased by 1.58/4.34 times and the small equivalent pore radius increased by 1.84/1.90 times, respectively. These results indicate that passive diffusion of hydrophilic solutes across an alveolar epithelium occurs via small and large equivalent pores, reflecting interactions of transmembrane proteins expressed in intercellular tight junctions of alveolar epithelial cells.

scholarly journals Targeting Pin1 for Modulation of Cell Motility and Cancer Therapy

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 359
Author(s):  
Hsiang-Hao Chuang ◽  
Yen-Yi Zhen ◽  
Yu-Chen Tsai ◽  
Cheng-Hao Chuang ◽  
Ming-Shyan Huang ◽  
...  
Keyword(s):  
Cancer Therapy ◽  
Tumor Suppressors ◽  
Protein Conformation ◽  
Genome Stability ◽  
Recent Progress ◽  
Multiple Roles ◽  
Cancer Development ◽  
Cancer Hallmarks ◽  
Underlying Mechanisms ◽  
And Function

Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1) specifically binds and isomerizes the phosphorylated serine/threonine-proline (pSer/Thr-Pro) motif, which leads to changes in protein conformation and function. Pin1 is widely overexpressed in cancers and plays an important role in tumorigenesis. Mounting evidence has revealed that targeting Pin1 is a potential therapeutic approach for various cancers by inhibiting cell proliferation, reducing metastasis, and maintaining genome stability. In this review, we summarize the underlying mechanisms of Pin1-mediated upregulation of oncogenes and downregulation of tumor suppressors in cancer development. Furthermore, we also discuss the multiple roles of Pin1 in cancer hallmarks and examine Pin1 as a desirable pharmaceutical target for cancer therapy. We also summarize the recent progress of Pin1-targeted small-molecule compounds for anticancer activity.

scholarly journals Senescence associated long non-coding RNA 1 regulates cigarette smoke-induced senescence of type II alveolar epithelial cells through sirtuin-1 signaling

2021 ◽  
Vol 49 (2) ◽  
pp. 030006052098604
Author(s):  
Dong Yuan ◽  
Yuanshun Liu ◽  
Mengyu Li ◽  
Hongbin Zhou ◽  
Liming Cao ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Cigarette Smoke ◽  
Alveolar Epithelial Cell ◽  
Alveolar Epithelial Cells ◽  
Lung Epithelial Cells ◽  
Sirtuin 1 ◽  
Type Ii ◽  
Alveolar Epithelial ◽  
Non Coding Rna ◽  
Long Non Coding Rna

Objective The primary aim of our study was to explore the mechanisms through which long non-coding RNA (lncRNA)-mediated sirtuin-1 (SIRT1) signaling regulates type II alveolar epithelial cell (AECII) senescence induced by a cigarette smoke-media suspension (CSM). Methods Pharmacological SIRT1 activation was induced using SRT2104 and senescence-associated lncRNA 1 (SAL-RNA1) was overexpressed. The expression of SIRT1, FOXO3a, p53, p21, MMP-9, and TIMP-1 in different groups was detected by qRT-PCR and Western blotting; the activity of SA-β gal was detected by staining; the binding of SIRT1 to FOXO3a and p53 gene transcription promoters was detected by Chip. Results We found that CSM increased AECII senescence, while SAL-RNA1 overexpression and SIRT1 activation significantly decreased levels of AECII senescence induced by CSM. Using chromatin immunoprecipitation, we found that SIRT1 bound differentially to transcriptional complexes on the FOXO3a and p53 promoters. Conclusion Our results suggested that lncRNA-SAL1-mediated SIRT1 signaling reduces senescence of AECIIs induced by CSM. These findings suggest a new therapeutic target to limit the irreversible apoptosis of lung epithelial cells in COPD patients.

Transforming growth factor-alpha enhances alveolar epithelial cell repair in a new in vitro model

1994 ◽  
Vol 267 (6) ◽  
pp. L728-L738 ◽  
Author(s):  
F. Kheradmand ◽  
H. G. Folkesson ◽  
L. Shum ◽  
R. Derynk ◽  
R. Pytela ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epithelial Cell ◽  
Wound Repair ◽  
Wound Closure ◽  
Transforming Growth Factor ◽  
Alveolar Epithelial Cell ◽  
Alveolar Epithelial ◽  
Factor Alpha ◽  
Vitro Model

Alveolar epithelial type II cells are essential for regenerating an intact alveolar barrier after destruction of type I cells in vivo. The first objective of these experimental studies was to develop an in vitro model to quantify alveolar epithelial cell wound repair. The second objective was to investigate mechanisms of alveolar epithelial cell wound healing by studying the effects of serum and transforming growth factor-alpha (TGF-alpha) on wound closure. Primary cultures of rat alveolar type II cells were prepared by standard methods and grown to form confluent monolayers in 48 h. Then a wound was made by denuding an area (mean initial area of 2.1 +/- 0.6 mm2) of the monolayer. Re-epithelialization of the denuded area over time in the presence or absence of serum was measured using quantitative measurements from time-lapse video microscopy. The half time of wound healing was significantly enhanced in the presence of serum compared with serum-free conditions (2.4 +/- 0.2 vs. 17.4 +/- 0.8 h, P < 0.001). We then tested the hypothesis that TGF-alpha is an important growth factor for stimulating wound repair of alveolar epithelial cells. Exogenous addition of TGF-alpha in serum-free medium resulted in a significantly more rapid wound closure, and, furthermore, the addition of a monoclonal antibody to TGF-alpha in the presence of serum significantly decreased fourfold the rate of wound closure. Measurement of internuclear cell distance confirmed that both cell motility and cell spreading were responsible for closure of the wound. These data demonstrate that 1) the mechanisms of alveolar cell repair can be studied in vitro and that 2) TGF-alpha is a potent growth factor that enhances in vitro alveolar epithelial cell wound closure.

EXTRACELLULAR MATRIX-DRIVEN ALVEOLAR EPITHELIAL CELL DIFFERENTIATION IN VITRO

2005 ◽  
Vol 31 (5) ◽  
pp. 461-482 ◽  
Author(s):  
Colin E. Olsen ◽  
Brant E. Isakson ◽  
Gregory J. Seedorf ◽  
Richard L. Lubman ◽  
Scott Boitano
Keyword(s):  
Extracellular Matrix ◽  
Cell Differentiation ◽  
Epithelial Cell ◽  
Alveolar Epithelial Cell ◽  
Alveolar Epithelial ◽  
Epithelial Cell Differentiation
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