scholarly journals Suppression of Rcn3 in the alveolar epithelial cells may have beneficial effect against COPD

2020 ◽  
Author(s):  
Qianyu Zhang ◽  
Tong Wang ◽  
Jiawei Jin ◽  
Xiaoqian Shi ◽  
Zhenru Ma ◽  
...  
Keyword(s):  
Beneficial Effect ◽  
Secretory Pathway ◽  
Alveolar Epithelial Cell ◽  
Critical Role ◽  
Airflow Obstruction ◽  
Alveolar Epithelial Cells ◽  
Conditional Knockout ◽  
Chronic Obstructive ◽  
Alveolar Epithelial ◽  
Copd Patients

Abstract Background: Chronic obstructive pulmonary disease (COPD) is a highly prevalent lung disease worldwide and imposes increasing disease burdens globally. COPD is characterized by irreversible airflow obstruction. Emphysema is one of the primary pathological features causing the irreversible decline of pulmonary function, while the precise mechanisms behind emphysema remain unclear. Reticulocalbin 3 (Rcn3) is an endoplasmic reticulum (ER) lumen protein localized in the secretory pathway of living cells. We have reported that Rcn3 in type II alveolar epithelial cell (AECIIs) plays a critical role in perinatal lung development and bleomycin-induced lung injury-repair. Since is associated with alveolar epithelial disruption, Rcn3 might be involved in the development of emphysema during COPD. Materials and Methods : We examined Rcn3 expression in lung specimens from patients (44 COPD patients and 26 non-COPD control patients) undergoing lung lobectomy or pneumonectomy. Mouse models of COPD and emphysema were established by cigarette smoke (CS) exposure and intratracheal installation of pancreatic porcine elastase (PPE), respectively. Rcn3 expression was detected in the lung tissues from these mice. Furthermore, conditional knockout (CKO) mice with Rcn3 deletion specific to AECIIs, were used to explore the role of Rcn3 in PPE-induced emphysema progression. Rcn3 protein expression in lung tissues were evaluated by Western blot and immunohistochemistry. Rcn3 mRNA expression in lung tissues was detected by qPCR.Results : Compared with non-COPD patients, Rcn3 expression was significantly increased in the lung specimens from COPD patients. Rcn3 expression was also significantly up-regulated in the lung tissues from COPD mice and emphysematous mice. Moreover, selective ablation of Rcn3 in AEC IIs significantly alleviated severity of the mouse emphysema in response to intratracheal installation of PPE.Conclusions: Our data, for the first time, indicated that Rcn3 in AECIIs might play a role in modulating the progression of emphysema, and thus be involved in the development of COPD. Suppression of Rcn3 expression in AECIIs may have a beneficial effect on COPD.This work was supported by National Natural Science Foundation of China (No. 81641004).

scholarly journals GM-CSF and the impaired pulmonary innate immune response following hyperoxic stress

2006 ◽  
Vol 291 (6) ◽  
pp. L1246-L1255 ◽  
Author(s):  
Carlos E. O. Baleeiro ◽  
Paul J. Christensen ◽  
Susan B. Morris ◽  
Michael P. Mendez ◽  
Steven E. Wilcoxen ◽  
...  
Keyword(s):  
Immune Response ◽  
Epithelial Cell ◽  
Innate Immune Response ◽  
Alveolar Epithelial Cell ◽  
Critical Role ◽  
Innate Immune ◽  
Alveolar Epithelial Cells ◽  
Bacterial Colony ◽  
Alveolar Epithelial ◽  
Gm Csf

We have previously demonstrated that mice exposed to sublethal hyperoxia (an atmosphere of >95% oxygen for 4 days, followed by return to room air) have significantly impaired pulmonary innate immune response. Alveolar macrophages (AM) from hyperoxia-exposed mice exhibit significantly diminished antimicrobial activity and markedly reduced production of inflammatory cytokines in response to stimulation with LPS compared with AM from control mice in normoxia. As a consequence of these defects, mice exposed to sublethal hyperoxia are more susceptible to lethal pneumonia with Klebsiella pneumoniae than control mice. Granulocyte/macrophage colony-stimulating factor (GM-CSF) is a growth factor produced by normal pulmonary alveolar epithelial cells that is critically involved in maintenance of normal AM function. We now report that sublethal hyperoxia in vivo leads to greatly reduced alveolar epithelial cell GM-CSF expression. Systemic treatment of mice with recombinant murine GM-CSF during hyperoxia exposure preserved AM function, as indicated by cell surface Toll-like receptor 4 expression and by inflammatory cytokine secretion following stimulation with LPS ex vivo. Treatment of hyperoxic mice with GM-CSF significantly reduced lung bacterial burden following intratracheal inoculation with K. pneumoniae, returning lung bacterial colony-forming units to the level of normoxic controls. These data point to a critical role for continuous GM-CSF activity in the lung in maintenance of normal AM function and demonstrate that lung injury due to hyperoxic stress results in significant impairment in pulmonary innate immunity through suppression of alveolar epithelial cell GM-CSF expression.

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 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.

scholarly journals TRIM72 is required for effective repair of alveolar epithelial cell wounding

2014 ◽  
Vol 307 (6) ◽  
pp. L449-L459 ◽  
Author(s):  
Seong Chul Kim ◽  
Thomas Kellett ◽  
Shaohua Wang ◽  
Miyuki Nishi ◽  
Nagaraja Nagre ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Molecular Mechanisms ◽  
Striated Muscle ◽  
Alveolar Epithelial Cell ◽  
Alveolar Epithelial Cells ◽  
Lung Cells ◽  
Alveolar Epithelial ◽  
High Tidal Volume Ventilation

The molecular mechanisms for lung cell repair are largely unknown. Previous studies identified tripartite motif protein 72 (TRIM72) from striated muscle and linked its function to tissue repair. In this study, we characterized TRIM72 expression in lung tissues and investigated the role of TRIM72 in repair of alveolar epithelial cells. In vivo injury of lung cells was introduced by high tidal volume ventilation, and repair-defective cells were labeled with postinjury administration of propidium iodide. Primary alveolar epithelial cells were isolated and membrane wounding and repair were labeled separately. Our results show that absence of TRIM72 increases susceptibility to deformation-induced lung injury whereas TRIM72 overexpression is protective. In vitro cell wounding assay revealed that TRIM72 protects alveolar epithelial cells through promoting repair rather than increasing resistance to injury. The repair function of TRIM72 in lung cells is further linked to caveolin 1. These data suggest an essential role for TRIM72 in repair of alveolar epithelial cells under plasma membrane stress failure.

M2 macrophages have unique transcriptomes but conditioned media does not promote profibrotic responses in lung fibroblasts or alveolar epithelial cells in vitro

2021 ◽  
Author(s):  
Elissa M Hult ◽  
Stephen James Gurczynski ◽  
Bethany B Moore
Keyword(s):  
Pulmonary Fibrosis ◽  
Alveolar Epithelial Cell ◽  
Conditioned Media ◽  
Alveolar Epithelial Cells ◽  
Lung Fibroblasts ◽  
M2 Macrophage ◽  
M2 Macrophages ◽  
Alveolar Epithelial ◽  
Fibroblast Migration

Macrophages are critical regulators of pulmonary fibrosis. Their plasticity, proximity, and ability to crosstalk with structural cells of the lung make them a key cell type of interest in the regulation of lung fibrosis. Macrophages can express a variety of phenotypes which have been historically represented through an "M1-like" to "M2-like" delineation. In this classification, M1-like macrophages are proinflammatory and have increased phagocytic capacity compared to alternatively activated M2-like macrophages that are profibrotic and are associated with wound healing. Extensive evidence in the field in both patients and animal models align pulmonary fibrosis with M2 macrophages. In this paper, we performed RNAseq to fully characterize M1 vs. M2-skewed bone marrow-derived macrophages (BMDMs) and investigated the profibrotic abilities of M2 BMDM conditioned media (CM) to promote fibroblast migration, proliferation, alveolar epithelial cell (AEC) apoptosis, and mRNA expression of key fibrotic genes in both fibroblasts and in AECs. Although M2 CM-treated fibroblasts had increased migration and M2 CM-treated fibroblasts and AECs had increased expression of profibrotic proteins over M1 CM-treated cells, all differences can be attributed to M2 polarization reagents IL-4 and IL-13 also present in the CM. Collectively, these data suggest that the profibrotic effects associated with M2 macrophage CM in vitro are attributable to effects of polarization cytokines rather than additional factors secreted in response to those polarizing cytokines.

Silica directly increases permeability of alveolar epithelial cells

1990 ◽  
Vol 68 (4) ◽  
pp. 1354-1359 ◽  
Author(s):  
R. K. Merchant ◽  
M. W. Peterson ◽  
G. W. Hunninghake
Keyword(s):  
Epithelial Cells ◽  
Cell Injury ◽  
Alveolar Epithelial Cell ◽  
Alveolar Epithelium ◽  
Alveolar Epithelial Cells ◽  
Dependent Manner ◽  
Alveolar Epithelial ◽  
Lactate Dehydrogenase Release ◽  
Capillary Membrane

Alveolar epithelial cell injury and increased alveolar-capillary membrane permeability are important features of acute silicosis. To determine whether silica particles contribute directly to this increased permeability, we measured paracellular permeability of rat alveolar epithelium after exposure to silica, in vitro, using markers of the extracellular space. Silica (Minusil) markedly increased permeability in a dose- and time-dependent manner. This was not the result of cytolytic injury, because lactate dehydrogenase release from monolayers exposed to silica was not increased. Pretreatment of the silica with serum, charged dextrans, or aluminum sulfate blocked the increase in permeability. Scanning electron microscopy demonstrated adherence of the silica to the surface of the alveolar epithelial cells. Thus silica can directly increase permeability of alveolar epithelium.

Alveolar epithelial cell inhibition of fibroblast proliferation is regulated by MCP-1/CCR2 and mediated by PGE2

2003 ◽  
Vol 284 (2) ◽  
pp. L342-L349 ◽  
Author(s):  
Bethany B. Moore ◽  
Marc Peters-Golden ◽  
Paul J. Christensen ◽  
Vibha Lama ◽  
William A. Kuziel ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Alveolar Epithelial Cell ◽  
Alveolar Epithelial Cells ◽  
Fibroblast Proliferation ◽  
Monocyte Chemoattractant Protein 1 ◽  
Monocyte Chemoattractant ◽  
Alveolar Epithelial ◽  
Sensitive Factor ◽  
Cc Chemokine Receptor 2 ◽  
Cell Inhibition

CC chemokine receptor 2 (CCR2) −/− mice are protected from experimental pulmonary fibrosis, a disease increasingly recognized as being mediated by dysfunctional interactions between epithelial cells and fibroblasts. We have sought to investigate the interactions between alveolar epithelial cells (AECs) and fibroblasts in these fibrosis-resistant (CCR2 −/−) and fibrosis-sensitive (CCR2 +/+) mice. AECs from CCR2 −/− mice suppress fibroblast proliferation more than AECs from CCR2 +/+ mice (77 vs. 43%). Exogenous administration of the CCR2 ligand monocyte chemoattractant protein-1 (MCP-1) to the fibroblast-AEC cocultures reverses the suppression mediated by CCR2 +/+ AECs but has no effect with CCR2 −/− AECs. MCP-1 regulates AEC function but not fibroblast function. AEC inhibition of fibroblast proliferation was mediated by a soluble, aspirin-sensitive factor. Accordingly, AECs from CCR2 −/− mice produce greater quantities of PGE2 than do AECs from CCR2 +/+ mice, and MCP-1 inhibits AEC-derived PGE2synthesis. Diminished PGE2 production by AECs results in enhanced fibroproliferation. Thus an important profibrotic mechanism of MCP-1/CCR2 interactions is to limit PGE2 production in AECs after injury, thus promoting fibrogenesis.

Voltage-gated proton channels help regulate pHi in rat alveolar epithelium

2005 ◽  
Vol 288 (2) ◽  
pp. L398-L408 ◽  
Author(s):  
Ricardo Murphy ◽  
Vladimir V. Cherny ◽  
Deri Morgan ◽  
Thomas E. DeCoursey
Keyword(s):  
Epithelial Cells ◽  
Ph Regulation ◽  
Alveolar Epithelial Cell ◽  
Alveolar Epithelium ◽  
Alveolar Epithelial Cells ◽  
Proton Channel ◽  
Resting Cells ◽  
Proton Channels ◽  
Voltage Gated ◽  
Alveolar Epithelial

Voltage-gated proton channels are expressed highly in rat alveolar epithelial cells. Here we investigated whether these channels contribute to pH regulation. The intracellular pH (pHi) was monitored using BCECF in cultured alveolar epithelial cell monolayers and found to be 7.13 in nominally HCO3−-free solutions [at external pH (pHo) 7.4]. Cells were acid-loaded by the NH4+ prepulse technique, and the recovery was observed. Under conditions designed to eliminate the contribution of other transporters that alter pH, addition of 10 μM ZnCl2, a proton channel inhibitor, slowed recovery about twofold. In addition, the pHi minimum was lower, and the time to nadir was increased. Slowing of recovery by ZnCl2 was observed at pHo 7.4 and pHo 8.0 and in normal and high-K+ Ringer solutions. The observed rate of Zn2+-sensitive pHi recovery required activation of a small fraction of the available proton conductance. We conclude that proton channels contribute to pHi recovery after an acid load in rat alveolar epithelial cells. Addition of ZnCl2 had no effect on pHi in unchallenged cells, consistent with the expectation that proton channels are not open in resting cells. After inhibition of all known pH regulators, slow pHi recovery persisted, suggesting the existence of a yet-undefined acid extrusion mechanism in these cells.

Rv3351c, aMycobacterium tuberculosisgene that affects bacterial growth and alveolar epithelial cell viability

2015 ◽  
Vol 61 (12) ◽  
pp. 938-947 ◽  
Author(s):  
Rebecca L. Pavlicek ◽  
Kari Fine-Coulson ◽  
Tuhina Gupta ◽  
Frederick D. Quinn ◽  
James E. Posey ◽  
...  
Keyword(s):  
Alveolar Epithelial Cell ◽  
Alveolar Epithelial Cells ◽  
Host Cells ◽  
Gene Products ◽  
Type Ii ◽  
Intracellular Replication ◽  
Cytotoxic Effects ◽  
Alveolar Epithelial ◽  
Type Ii Pneumocyte

Despite the interactions known to occur between various lower respiratory tract pathogens and alveolar epithelial cells (AECs), few reports examine factors influencing the interplay between Mycobacterium tuberculosis bacilli and AECs during infection. Importantly, in vitro studies have demonstrated that the M. tuberculosis hbha and esxA gene products HBHA and ESAT6 directly or indirectly influence AEC survival. In this report, we identify Rv3351c as another M. tuberculosis gene that impacts the fate of both the pathogen and AEC host. Intracellular replication of an Rv3351c mutant in the human AEC type II pneumocyte cell line A549 was markedly reduced relative to the complemented mutant and parent strain. Deletion of Rv3351c diminished the release of lactate dehydrogenase and decreased uptake of trypan blue vital stain by host cells infected with M. tuberculosis bacilli, suggesting attenuated cytotoxic effects. Interestingly, an isogenic hbha mutant displayed reductions in AEC killing similar to those observed for the Rv3351c mutant. This opens the possibility that multiple M. tuberculosis gene products interact with AECs. We also observed that Rv3351c aids intracellular replication and survival of M. tuberculosis in macrophages. This places Rv3351c in the same standing as HBHA and ESAT6, which are important factors in AECs and macrophages. Defining the mechanism(s) by which Rv3351c functions to aid pathogen survival within the host may lead to new drug or vaccine targets.

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