4/10/03

Anthrax Simulation, Inhalation form (diffuse initial injury).

Antibiotic effect from Time 2 to 29 (14 days), reduces inf by 0.2 in inj-function.

Modified from NIGMS3.5

Anthrax bacillus characterized by production of exotoxins.

3 factors:

1) Edema factor: Produced at + infection in inj-function

Diffuses at 0.1

Evaporates at 0.7

2) Lethal factor: Produced at + infection in inj-function

Diffuses at 0.1

Evaporates at 0.7

3) Protective antigen: Produced at + infection in inj-function

Diffuses at 0.1

Evaporates at 0.7

2 toxins produced as a result of these three factors.

1) Edema toxin. This is Edema factor + Protective antigen / 10. Chemoattracts PMNs=> PMN-sniff responds to PAF + IL-8 + edema-toxin

Suppresses PMN burst=> In PMN-burst superoxide set at max 0 (superoxide + (max 1 (TNF)) - edema-toxin)

Increases tissue edema and no-reflow EC damage=> in ec-function all oxy updates subtract edema-toxin/1000

2) Lethal toxin. This is Letal factor + Protective antigen / 10. If lethal-toxin > 0, then shunts monos to pathway that:

Reduces mono-age to min 10 mono-age-1 and

Activates monos and

Modifies production of IL-1 and TNF to + lethal-toxin and

Adds turtle variables "Stored-IL-1" and "Stored-TNF" that update at same rate as IL-1 and TNF, and is released upon mono-death.

Both toxins require Protective antigen to have an effect.

NOTE! Make sure that sequence of commands within functions do not "double update" variables (ran into this problem with IL-10 production. Variables that are involved in updating other variables whould be updated afterwards.

Current effect of GCSF on pmn-marrow is to repeat pmn generation 1 + int (total-GCSF/10). This seems to produce an okay leukocytosis.

RNGs OFF

1 step = 7 minutes

1 time = 100 steps = 700 minutes = 11.67 hours

1 loop = 58 time = 5800 steps = 40600 minutes = 28.19 days

Looping run with increases of IIN by 50 each 100 loops.

Infection parameters changed. Reduces oxy by infection value, produces endotoxin at infection value/10.

New system endpoint: time at which death threshold is reached and and system dies. Death threshold is set at 80% of total baseline sytem oxy, or 10201 * .80 = 8160.8. This determination is made after in second sequence of the "go1" command (right after the check of "time"), and if greater than death threshold will end the loop, print the oxy-deficit, the total-infection, and the time of death (time of death = time + (step/100) ).

Output is oxy-deficit, total-infection and time (at end of time loop, either 58 if system survives or < if dies before).

Modes:

1= Injury

2= Endotoxin

3= PAF

4= TNF

5= IL-1

6= sTNFr

7= INF-g

8= IL-10

9= IL-1ra

10= IL-8

11= IL-12

12= IL-4

13= GCSF

14= superoxide

15= nitricoxide

16= edema-toxin

17= lethal-toxin

PMN-migration linked to TNF + IL-1 + GCSF - IL-10 > 0

PMNs prime (set wbc-stick = IL-1 + TNF) at TNF + PAF > 1

Primed PMNs update IL-1ra at IL-1ra + 1

PMN apoptosis is calculated thusly:

in PMN-burst, pmn-pcd is updated at

pmn-pcd - 1 + max 0 ((TNF + INF-g + GCSF - IL-10) / 10)

Infection effect is to reduce oxy by value of infection to minimum of 0. Infection value is still capped at 100. Increase in infection is updated at +0.1. Spread is still linked to threshold of Infection >= 100. Infection spread increases infection variable by 2 on a random Moore neighborhood. This spread fits better with time course. Infection is also decreased by value of superoxide to reflect varible efficacy of PMN-burst.

Recurrent baseline infection occurs every 100 steps (at step=99). Each hit produces 5 random patches of infection 100. This function is in ec-function.

Endotoxin is produced in inj-function upon infection killing by superoxide (if superoxide > 0 then endotoxin = endotoxin + superoxide); max 100, min 0, diffuses at 1.0, evaporates at 0.8

Superoxide is produced during PMN-burst at superoxide + max 1 TNF, diffuses at 0.2, evaporates at 0.5. It reduces infection by superoxide (and thus produces endotoxin at + superoxide) and reduces EC oxy by superoxide.

Nitricoxide produced by ECs at 0.05 in ischemic phase. If nitricoxide < 1 then it is added to oxy in patch-inj-spread. This simulates eNOS production that is beneficial. It counters the oxy reduction in ischemia, simulating cytoprotective effect.

Nitricoxide also produced in mono function "heal" and PMN function "pmn-burst" at nitricoxide + 1. This simulates iNOS function.

Diffuses at 0.2, evaporates at 0.6

ECs are actived by Endotoxin >= 1 or oxy < 60. EC-activated will:

1) setec-roll ec-roll + 1

2) setec-stick ec-stick + 1

3) setPAF PAF + 1

4) setIL-8 IL-8 + TNF + IL-1

5) setnitricoxide nitricoxide + 0.05

PAF is produced by ECs in ec-activated, diffused at .50 and evaporates at 0.8.

PMN chemotaxis is now based on PAF + IL-8

Age for PMNs and Monos changed to 50 instead of 100, PMN-pcd to 10 from 20, with cooresponding change in PMN/Mono-generation rates. This is to bring time scales more in bearing with half-lifes of cytokines (about 7 minutes/step).

PMN apoptosis is added as pmn-pcd variable. After pmn-migrate>0 and pmns do into "pmn-burst" pmn-age gets set to pmn-pcd, which starts at 10 and decreases by 1 + max 0 ((TNF + INF-g + GCSF - IL-10) / 10) per step.

PMNs are also activated by TNF and PAF

Monos now have turtle-variables TNFr and IL-1r.

TNFr has bimodal distribution, dependent upon level of sTNFr. At lower levels of sTNFr (which actively binds TNFr, update is min 100 (TNF +sTNFr). At higher levels of sTNFr (where sTNFr is competetive to TNF) update is max 0 (TNF-sTNFr).

IL-1r is set at min 100 (IL-1 - IL-1ra - sIL-1r), which simulates competetive binding of IL-1ra and sIL-1r to IL-1.

Monos have an "activation" variable which determines mono responsiveness. It is set at (endotoxin + PAF + INF-g - IL-10). If activation is > 0 then monos are "Proinflammatory." If activation is < 0 then monas are "Immunesuppressed."

Proinflammatory monos (in order):

1) Produces GCSF at tsetGCSF (GCSF + endotoxin + PAF + TNF + INF-G). Diffuses at 1.0, evaporates at 0.95.

2) Produces IL-8 at tsetIL-1 max 0 (IL-8 + TNF + IL-1), diffuses at 0.6, evaporates at 0.9. Chemotactic for PMNs

3) Produces IL-12 at tsetIL-12 IL-12 + (TNF + IL-1) / 2, diffuses as 0.8, evaporates at 0.99. Changes TH0 to TH1.

4) Produces IL-10 at tsetIL-10 IL-10 + (TNF + IL-1) / 2, Diffuses at 0.8, evaporates at 0.95.

5) Produce IL-1 at tsetIL-1 max 0 (IL-1{prior level IL-1} + endotoxin + PAF {Proinflam effects of both} + IL-1r{reflects activation and feedback of IL-1r status} + TNF). It diffuses at 0.6, evaporates at 0.9.

6) Produce TNF at tsetTNF max 0 (TNF{prior level TNF} + endotoxin + PAF {proinflam effects of both on monos} + TNFr{reflects activation and feedback of TNFr status}) Diffuses at 0.6, evaporates at 0.9.

Immunesuppressed monos:

1) Produce IL-10 at tsetIL-10 IL-10 + (TNF + IL-1) / 2

Monos now need adhesion similar to PMNs to heal. Use variables wbc-roll, wbc-stick and wbc-migrate.

sTNFr is sTNFr + TNF/2. Diffuses at 0.8, evaporates at 0.9.

IL-1ra is produced in mono-function = IL-1ra + IL-1, diffuses at 0.8, evaporates at 0.8.

sIL-1r is produced in mono-function = sIL-1r + (IL-1r / 2).

IL-10 produced in both Mono-function irrespective of activation level as (IL-10 + (TNF + IL-1), and in TH2-function as (IL-10 + IL-10).

TH1 cells produce INF-g.

TH2 cells produce IL-10 and IL-4

Differentiation from TH0 is determined by:

If random ((IL-12 + INF-g) * 100) > random ((Il-4 + IL-10) * 100), then activation +1

If random (IL-10 + IL-4) > random (IL-12 + INF-g), then activation -1.

This is done using holding variables pro-TH1/TH2 and rTH1/TH2 {the randomized values}

When activation >=10 then change to TH1

When activation <=-10 then change to TH2

IL-4 produced by TH2-function as (IL-4 + IL-10), diffuses at 0.8 evaporates at 0.95.

INF-g produced in TH1-function as (INF-g + INF-g + IL-12 +TNF + IL-1), diffuses at 0.8, evaporates at 0.9.

IL-8 is chemotactic for PMNs. It is produced by ECs at IL-8 + TNF + IL-1 in both ischemic and infarcted states, and it is produced by Monos at tsetIL-1 max 0 (IL-8 + TNF + IL-1), diffuses at 0.6, evaporates at 0.9.

GCSF has multiple effects.

1) Incorporated into pmn-apoptosis function (+ max 1 (TNF + INF-g + GCSF - IL-10) / 10

2) Incorporated into WBC-migrate = (TNF + IL-1 + GCSF - IL-10)

3) Affects PMN count in pmn-marrow-function, repeating generation by max 1 int (total-GCSF / 10). Note this is a global function. This seems to give appropriate levels of leukocytosis