On the Role of Continuum Models in Mechanobiology

2000 ◽  
Author(s):  
R. D. Kamm ◽  
A. K. McVittie ◽  
M. Bathe
Keyword(s):  
Basolateral Membrane ◽  
Biological Response ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Stress Distributions ◽  
Dynamic Simulations ◽  
Mechanics Model ◽  
A Cell ◽  
Underlying Mechanisms

Abstract Models of cellular and subcellular mechanics are essential in gaining an understanding of the link between forces applied to a cell and its biological response. Various approaches can be used to construct these models, but one that holds considerable promise is through the use of continuum solid and fluid mechanics, coupled when necessary with molecular dynamic simulations. Here we present a continuum mechanics model of the effects of normal stress applied to a layer of airway epithelial cells. The model predicts widely differing stress distributions associated with basolateral membrane deformation, intercellular flow, or mechanical forcing by other methods such as in the use of adherent beads. When coupled with experimental results obtained from cell culture, these simulations can help to identify the site and possibly the underlying mechanisms of mechanotransduction. We also present some hypotheses concerning the nature of mechanotransduction at the molecular scale.

scholarly journals Pulmonary fibrosis distal airway epithelia are dynamically and structurally dysfunctional

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ian T. Stancil ◽  
Jacob E. Michalski ◽  
Duncan Davis-Hall ◽  
Hong Wei Chu ◽  
Jin-Ah Park ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Airway Epithelium ◽  
Cell Types ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Airway Epithelia ◽  
Chronic Lung Diseases ◽  
Distal Airway ◽  
Signaling Axis

AbstractThe airway epithelium serves as the interface between the host and external environment. In many chronic lung diseases, the airway is the site of substantial remodeling after injury. While, idiopathic pulmonary fibrosis (IPF) has traditionally been considered a disease of the alveolus and lung matrix, the dominant environmental (cigarette smoking) and genetic (gain of function MUC5B promoter variant) risk factor primarily affect the distal airway epithelium. Moreover, airway-specific pathogenic features of IPF include bronchiolization of the distal airspace with abnormal airway cell-types and honeycomb cystic terminal airway-like structures with concurrent loss of terminal bronchioles in regions of minimal fibrosis. However, the pathogenic role of the airway epithelium in IPF is unknown. Combining biophysical, genetic, and signaling analyses of primary airway epithelial cells, we demonstrate that healthy and IPF airway epithelia are biophysically distinct, identifying pathologic activation of the ERBB-YAP axis as a specific and modifiable driver of prolongation of the unjammed-to-jammed transition in IPF epithelia. Furthermore, we demonstrate that this biophysical state and signaling axis correlates with epithelial-driven activation of the underlying mesenchyme. Our data illustrate the active mechanisms regulating airway epithelial-driven fibrosis and identify targets to modulate disease progression.

PBA increases CFTR expression but at high doses inhibits Cl−secretion in Calu-3 airway epithelial cells

1999 ◽  
Vol 277 (4) ◽  
pp. L700-L708 ◽  
Author(s):  
Johannes Loffing ◽  
Bryan D. Moyer ◽  
Donna Reynolds ◽  
Bruce A. Stanton
Keyword(s):  
Protein Expression ◽  
Apical Membrane ◽  
Basolateral Membrane ◽  
Airway Epithelial Cells ◽  
Cell Phenotype ◽  
Apical Plasma Membrane ◽  
Airway Epithelial ◽  
High Concentration ◽  
Cycle Enzyme ◽  
Cf Transmembrane Conductance Regulator

Sodium 4-phenylbutyrate (PBA), a short-chain fatty acid, has been approved to treat patients with urea cycle enzyme deficiencies and is being evaluated in the management of sickle cell disease, thalassemia, cancer, and cystic fibrosis (CF). Because relatively little is known about the effects of PBA on the expression and function of the wild-type CF transmembrane conductance regulator (wt CFTR), the goal of this study was to examine the effects of PBA and related compounds on wt CFTR-mediated Cl−secretion. To this end, we studied Calu-3 cells, a human airway cell line that expresses endogenous wt CFTR and has a serous cell phenotype. We report that chronic treatment of Calu-3 cells with a high concentration (5 mM) of PBA, sodium butyrate, or sodium valproate but not of sodium acetate reduced basal and 8-(4-chlorophenylthio)-cAMP-stimulated Cl−secretion. Paradoxically, PBA enhanced CFTR protein expression 6- to 10-fold and increased the intensity of CFTR staining in the apical plasma membrane. PBA also increased protein expression of Na+-K+-ATPase. PBA reduced CFTR Cl−currents across the apical membrane but had no effect on Na+-K+-ATPase activity in the basolateral membrane. Thus a high concentration of PBA (5 mM) reduces Cl−secretion by inhibiting CFTR Cl−currents across the apical membrane. In contrast, lower therapeutic concentrations of PBA (0.05–2 mM) had no effect on cAMP-stimulated Cl−secretion across Calu-3 cells. We conclude that PBA concentrations in the therapeutic range are unlikely to have a negative effect on Cl−secretion. However, concentrations >5 mM might reduce transepithelial Cl−secretion by serous cells in submucosal glands in individuals expressing wt CFTR.

Innate immune response in CF airway epithelia: hyperinflammatory?

2006 ◽  
Vol 291 (2) ◽  
pp. C218-C230 ◽  
Author(s):  
Terry E. Machen
Keyword(s):  
Immune Response ◽  
Epithelial Cells ◽  
Innate Immune Response ◽  
Cellular Signaling ◽  
Basolateral Membrane ◽  
Airway Epithelial Cells ◽  
Innate Immune ◽  
Airway Epithelial ◽  
Airway Epithelia ◽  
Intracellular Ca

The lack of functional cystic fibrosis (CF) transmembrane conductance regulator (CFTR) in the apical membranes of CF airway epithelial cells abolishes cAMP-stimulated anion transport, and bacteria, eventually including Pseudomonas aeruginosa, bind to and accumulate in the mucus. Flagellin released from P. aeruginosa triggers airway epithelial Toll-like receptor 5 and subsequent NF-κB signaling and production and release of proinflammatory cytokines that recruit neutrophils to the infected region. This response has been termed hyperinflammatory because so many neutrophils accumulate; a response that damages CF lung tissue. We first review the contradictory data both for and against the idea that epithelial cells exhibit larger-than-normal proinflammatory signaling in CF compared with non-CF cells and then review proposals that might explain how reduced CFTR function could activate such proinflammatory signaling. It is concluded that apparent exaggerated innate immune response of CF airway epithelial cells may have resulted not from direct effects of CFTR on cellular signaling or inflammatory mediator production but from indirect effects resulting from the absence of CFTRs apical membrane channel function. Thus, loss of Cl−, HCO3−, and glutathione secretion may lead to reduced volume and increased acidification and oxidation of the airway surface liquid. These changes concentrate proinflammatory mediators, reduce mucociliary clearance of bacteria and subsequently activate cellular signaling. Loss of apical CFTR will also hyperpolarize basolateral membrane potentials, potentially leading to increases in cytosolic [Ca2+], intracellular Ca2+, and NF-κB signaling. This hyperinflammatory effect of CF on intracellular Ca2+and NF-κB signaling would be most prominently expressed during exposure to both P. aeruginosa and also endocrine, paracrine, or nervous agonists that activate Ca2+signaling in the airway epithelia.

Role of size and composition of traffic and agricultural aerosols in the molecular responses triggered in airway epithelial cells

2011 ◽  
Vol 23 (11) ◽  
pp. 627-640 ◽  
Author(s):  
Val Stéphanie ◽  
Martinon Laurent ◽  
Cachier Hélène ◽  
Yahyaoui Abderrazak ◽  
Marfaing Hélène ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Molecular Responses

scholarly journals Asthma-associated genetic variants induce IL33 differential expression through an enhancer-blocking regulatory region

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ivy Aneas ◽  
Donna C. Decker ◽  
Chanie L. Howard ◽  
Débora R. Sobreira ◽  
Noboru J. Sakabe ◽  
...  
Keyword(s):  
Association Studies ◽  
Regulatory Region ◽  
Airway Epithelial Cells ◽  
Genome Wide Association Studies ◽  
Airway Epithelial ◽  
Allele Specific ◽  
Enhancer Blocking ◽  
Underlying Mechanisms

AbstractGenome-wide association studies (GWAS) have implicated the IL33 locus in asthma, but the underlying mechanisms remain unclear. Here, we identify a 5 kb region within the GWAS-defined segment that acts as an enhancer-blocking element in vivo and in vitro. Chromatin conformation capture showed that this 5 kb region loops to the IL33 promoter, potentially regulating its expression. We show that the asthma-associated single nucleotide polymorphism (SNP) rs1888909, located within the 5 kb region, is associated with IL33 gene expression in human airway epithelial cells and IL-33 protein expression in human plasma, potentially through differential binding of OCT-1 (POU2F1) to the asthma-risk allele. Our data demonstrate that asthma-associated variants at the IL33 locus mediate allele-specific regulatory activity and IL33 expression, providing a mechanism through which a regulatory SNP contributes to genetic risk of asthma.

scholarly journals The Virulence Potential of Livestock-Associated Methicillin-Resistant Staphylococcus aureus Cultured from the Airways of Cystic Fibrosis Patients

Toxins ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 360
Author(s):  
Janina Treffon ◽  
Sarah Ann Fotiadis ◽  
Sarah van Alen ◽  
Karsten Becker ◽  
Barbara C. Kahl
Keyword(s):  
Cystic Fibrosis ◽  
Staphylococcus Aureus ◽  
Airway Epithelial Cells ◽  
Farm Animals ◽  
Airway Epithelial ◽  
Methicillin Resistant ◽  
Virulence Potential ◽  
Airway Infections ◽  
Severe Infections

Staphylococcus aureus is one of the most common pathogens that infects the airways of patients with cystic fibrosis (CF) and contributes to respiratory failure. Recently, livestock-associated methicillin-resistant S. aureus (LA-MRSA), usually cultured in farm animals, were detected in CF airways. Although some of these strains are able to establish severe infections in humans, there is limited knowledge about the role of LA-MRSA virulence in CF lung disease. To address this issue, we analyzed LA-MRSA, hospital-associated (HA-) MRSA and methicillin-susceptible S. aureus (MSSA) clinical isolates recovered early in the course of airway infection and several years after persistence in this hostile environment from pulmonary specimens of nine CF patients regarding important virulence traits such as their hemolytic activity, biofilm formation, invasion in airway epithelial cells, cytotoxicity, and antibiotic susceptibility. We detected that CF LA-MRSA isolates were resistant to tetracycline, more hemolytic and cytotoxic than HA-MRSA, and more invasive than MSSA. Despite the residence in the animal host, LA-MRSA still represent a serious threat to humans, as such clones possess a virulence potential similar or even higher than that of HA-MRSA. Furthermore, we confirmed that S. aureus individually adapts to the airways of CF patients, which eventually impedes the success of antistaphylococcal therapy of airway infections in CF.

scholarly journals Protective role of Indoleamine 2,3 dioxygenase in Respiratory Syncytial Virus associated immune response in airway epithelial cells

Virology ◽  
2017 ◽  
Vol 512 ◽  
pp. 144-150 ◽  
Author(s):  
Devi Rajan ◽  
Raghavan Chinnadurai ◽  
Evan L. O'Keefe ◽  
Seyhan Boyoglu-Barnum ◽  
Sean O. Todd ◽  
...  
Keyword(s):  
Immune Response ◽  
Respiratory Syncytial Virus ◽  
Epithelial Cells ◽  
Protective Role ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Indoleamine 2,3 Dioxygenase ◽  
Syncytial Virus

Airway epithelial tight junctions and binding and cytotoxicity ofPseudomonas aeruginosa

1999 ◽  
Vol 277 (1) ◽  
pp. L204-L217 ◽  
Author(s):  
Alfred Lee ◽  
Dar Chow ◽  
Brian Haus ◽  
Wanru Tseng ◽  
David Evans ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Tight Junctions ◽  
Propidium Iodide ◽  
Time Course ◽  
Living Cells ◽  
Airway Epithelial Cells ◽  
Airway Epithelial ◽  
Basolateral Membranes ◽  
Free Edges

The role of tight junctions in the binding and cytoxicity of Pseudomonas aeruginosato apical or basolateral membranes of lung airway epithelial cells was tested with fluorescence microscopy on living cells. Binding of noncytotoxic P. aeruginosa strain O1 was assessed with P. aeruginosa that expressed green fluorescent protein. Binding of cytotoxic P. aeruginosa strain 6206 was assessed with FITC-labeled P. aeruginosa; cytotoxicity was determined from nuclear uptake of the impermeant dye propidium iodide. The role of direct contact of P. aeruginosa to epithelial cells was tested with filters with small (0.45-μm) or large (2.0-μm) pores. High transepithelial resistance ( Rt) Calu-3 and cultured bovine tracheal monolayers ( Rt> 1,000 Ω ⋅ cm2) bound P. aeruginosa very infrequently (<1 P. aeruginosa/100 cells) at the apical membrane, but P. aeruginosabound frequently to cells near “free edges” at holes, wounds, islands, and perimeters; cytotoxicity required direct interaction with basolateral membranes. Wounded high Rtepithelia showed increased P. aeruginosa binding and cytotoxicity at the free edges because basolateral membranes were accessible to P. aeruginosa, and dead and living cells near the wound bound P. aeruginosa similarly. Compared with high Rtepithelia, low RtCFT1 ( Rt= 100–200 Ω ⋅ cm2) and EGTA-treated Calu-3 monolayers were 25 times more susceptible to P. aeruginosa binding throughout the monolayer. Cytotoxicity to CFT1 cells (throughout the confluent monolayer, not only at the free edge) occurred after a shorter delay (0.25 vs. 2.0 h) and then five times faster than to Calu-3 cells, indicating that the time course of P. aeruginosa cytotoxicity may be limited by the rate of gaining access through tight junctions and that this occurred faster in low Rtthan in high Rtairway epithelia. Cytotoxicity appeared to occur in a sequential process that led first to a loss of fura 2 and a later uptake of propidium iodide. P. aeruginosa bound three times more frequently to regions between cells (tight junctions?) than to cell membranes of low RtCFT1 cells.

Sign in / Sign up

Export Citation Format

Share Document