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Shock2004_Gut_Epithelial_Barrier

by Gary An, MD (Submitted: 06/12/2006)

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WHAT IS IT?

===========

Gut Epithelial Cell Barrier-Function Model

This is an abstract model of Epithelial Cell barrier function. It is based on an epithelial cell culture model that looks at the effect of cellular tight junction status on permeability of the epithelial cell sheet. Each gridspace represents an epithelial cell that can exist in one of two states: "healthy" or "sick." "Healthy" cells have intact tight junctions represented by the yellow margin, "sick" cells have lost the tight junction proteins and have a black border. The agent rules present in an abstract form the sequence of synthesis of the proteins (and their precursors) that make up the tight junctions. In the "healthy" state (i.e. with tight junctions intact) the entire surface of epithelial cells is impermeable to the "solute."
Cells transition between "healthy" and "sick" by interruption of tight junction protein synthesis. The primary mediator of this is nitric oxide (NO). NO interrupts the synthetic pathways for the tight junction proteins. NO can either be directly added to the model (via the "Add-NO" button), or be produced by the epithelial cells via inducible nitric oxide synthetase (iNOS) in response to addition of a mix of pro-inflammatory cytokines (via the "Add-Cytomix" button).
The consequence of loss of tight junctions is that the areas of this loss become permeable to the "solute." This is a generic solute that, once the barrier becomes permeable, will diffuse through from a "lumen" "side" to a "penetrated" "side." The different "sides" of the epithelial cell barrier are represented by different patch variables, and can be seen by changing the "mode" by which the graphics screen scales it patch colors.
The first graph reports the relative levels of the "lumen" and "penetrated" solute. The second graph reports the levels of NO and Cytomix over time.

ARCHITECTURE AND INTERFACE

21 x 21 Grid of Epi Cells with Tight Junctions

Agents are Epi Cells with 2 possible Shapes: "epi-cell-health" with intact TJs and "epi-cell-sick" with disrupted TJs

5 Proteins needed for TJ formation:
1) Occludin
2) Claudin-1
3) ZO-1
4) ZO-2
5) ZO-3

TJ breakdown if these proteins are not appropriately at the Epi Cell Periphery

NO is a mediator for thw metabolism of the following proteins:
1) Decreases synthesis of ZO-1 mRNA, ZO-1, ZO-3, Occludin
2) Increases synthesis of Claudin-1
3) Impairs intracellular sublocalization of ZO-1, occludin and claudin-1

Treatment with pro-inflammatory cytokines (IL-1, TNF, INF-g = cytomix) activates iNOS and stimulates Epi Cell production of NO. Therefore all the above effects on TJ proteins are also seen with cytomix. Selective inhibition of iNOS reduces the effect of cytomix on permiability.

iNOS function is dependent upon proper activation of iNOSmRNA. This will be activated by presence of Cytomix (value > 0.0001). This acts through NF-kB which in turn activates iNOSmRNA production. Ethyl pyruvate and NAD+ both inhibit the action of NF-kB. Furthermore, iNOSmRNA can be inhibited by ethyl pyruvate. The addition of these substances can be controlled with sliders on the interface.

Timescales in paper are at 12, 24 and 48 hours.
1 step = 5 minutes
12 steps = 1 hour

Buttons to turn on:
1) Data Collection function
2) Looped runs to generate an experimental population
3) Addition of NO donor
4) Addition of Cytomix
5) Addition of NO scavenger

Sliders control:
1) Graphical Mode for display of different variables (See "How to use it")
2) Diffusion rate
3) Initial NO dose density
4) Initial Cytomix dose density
5) Degree of added Ethyl pyruvate
6) Degree of added NAD+

HOW TO USE IT

The "Setup" button resets the model, but does not clear the output screen.
The "Go" button runs the model.
The "Add-NO" button provides a one-time random distribution of NO to the model.
The "Add-Cytomix" button provides a one-time random distribution of Cytomix to the model.
The "Data" switch turns on/off the collection of "solute-lumen" and "solute-penetrated" at 12, 24 and 48 hours.
The "Loop-run" switch turns on/off the mode of multiple runs. The runs are set at 48 hours and can either be in "NO-Add" or "Cytomix-Add" (these determine whether the initial insult will be either NO or Cytomix).
The "Mode" slider determines what variable the patches are scaled to:
Mode=1: Shows Epithelial cells as either "healthy' or "sick" with focus on presence of tight junctions.
Mode=2: Shows amount of solute-lumen present.
Mode=3: Shows amount of solute-penetrated present.
Mode=4: Shows amount and distribution of NO.
Mode=5: Shows amount and distribution of Cytomix.
The "Diffusion Rate" slider changes the rate at which the solute will travel across the permeable areas of the model.
The "Initial NO" slider sets the amount of patches hit with NO.
The "Initial Cytomix" slider set the amount of patches hit with Cytomix.
THe "NO-scavenger" slider simulates the addition of a scavenger of NO, essentially removing NO from the affected areas. This reverses the protein synthesis blocking effect of NO. A value of "0" means no scavenger, a value of "1" adds it to the mix.
The "NO-mode" slider chooses NO as the recurrent insult if "Loop-run" switch is on.
The "Cytomix-mode" slider chooses Cytomix as the recurrent insult if "Loop-run" switch is on.
The "Ethyl pyruvate" and "NAD+" sliders set the amount of ethyl pyruvate and NAD+ that is administered to the model. It affects the update of NF-kB and iNOSmRNA.

To run the model:
Press "Setup"
Decide whether you want to run with incubation with NO ("Add-NO" swtich "On") or Cytomix ("Add-Cytomix" switch "On").
Choose whether you want to do looping runs ("Loop-run" switch) and/or whether you want to do data collection.
Choose levels of "Diffusion rate," "Initial-NO," and "Initial-Cytomix."
It is recommended that you start with Mode=1 to see the tight junction status. This slider can be changed on the fly, however, to see the distribution of the other variables.
It is recommended that you leave the "NO-scavenger" slider to "0" at first.
Press "Go" to run.

THINGS TO NOTICE

The loss of tight junctions will have a random pattern corresponding to the intitial distribution of NO/Cytomix. If the model is allowed to run beyond 48 hours, or the initial insult number is low, you can see the recovery of the tight junctions as the proteins are re-synthesized after levels of NO drop.
There will be a lag in tight junction loss if Cytmoix is used as the insult, accounting for the time it takes for iNOS to produce NO. Also notice the relative shapes of the NO and Cytmoix concentration curves in this situation.
The different modes were primarily used for de-bugging purposes to make sure that the patch variables were behaving as intended, but can be interesting to watch.

THINGS TO TRY

You can adjust the various sliders to increase/decrease the initial insult/diffusion rate. You can, after the model is running, add the NO-scavenger to attenuate the effect of the NO/Cytomix.

EXTENDING THE MODEL

As mentioned above, this is an abstract preliminary model. The rules for protein synthesis are very basic and work is being done to expand the scope of these rules. Additional activating/inhibiting variables may also be added.
The model here is also in the process of being integrated with an endothelial model using Netlogo 3-d Preview to create a bi-layer simulation of gut tissue function.

CREDITS

This model was produced by Gary An, MD from the Department of Trauma, Cook County Hospital, Chicago, IL, USA for a Poster presented at the 27th Annual Conference of the Shock Society, June 6, 2004:

An G, Delude R. Agent based model of cell culture epithelial barrier function: Using computer simulation in conjunction with a basic science model. Shock 2004; 21S2:s13.

Please email and questions or comments to docgca@earthlink.net

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