Biomedical Engineering Reference
In-Depth Information
teria as early as possible during this growth. The second phase is characterized
by phagocytic activation, an increase in the density of phagocytes to the site of
infection, and bacterial killing. The final phase is marked by increased accumu-
lation of anti-inflammatory mediators, decrease of PIC concentration, dissipa-
tion of phagocytes, and return to pre-inflammatory homeostasis.
With the parameters and initial conditions in the system described here, the
phagocytes typically detect the bacteria within an hour and are capable of halt-
ing the infection by killing the bacteria if the mean cycle time is substantially
longer than that time, even without the additional recruitment and chemotaxis
provided by PIC.
When the bacterial division time becomes comparable to the discovery
time, the phagocytes cannot adequately keep pace with the bacterial growth, and
the bacterial populations tend to grow virtually unchecked (Figure 2). Note that
the phagocyte density does increase in the intermediate stages of the process
(Figure 2A). The bacterial chemokines, however, because of their effective life-
time, are of such short range that they cannot increase local influx of phago-
cytes. Thus, the observed increase is due entirely to slowing of emigration by
virtue of phagocyte
capture
by the BC. Phagocytes wander in, but they do not
wander back out.
The phagocyte advantage is regained upon inclusion of PIC (Figure 3).
Once activated phagocytes produce PIC, the recruitment of new phagocytes is
substantially enhanced, and the effective radius of their capture is enlarged. Fur-
thermore, the saturating nature of the chemotactic response to superposed attrac-
tants ensures that the host-derived chemokines does not overwhelm the microbe-
derived factors and act as a decoy chemotactic destiny, as described above.
On the other hand, the positive feedback loop set up by PIC causes a sus-
tained local inflammation. The resolution of this inflammation requires breaking
this loop, a function served by the sPICR. The refractory cells are unresponsive
to further stimulation by PIC and shed soluble receptor, which binds and neu-
tralizes the PIC. Figure 4 shows that the evolution of the response with fully
sPICR-competent phagocytes is very similar to that of the sPICR-deficient
phagocytes in Figure 3 through the first two phases, but differs precisely at the
end of the activation phase and throughout the final phase—resolution.
4.
DISCUSSION AND CONCLUSION
The use of agent-continuous hybrid modeling for complex cellular systems
has really just begun; there is a great deal of work to be done in bringing greater
detail to the components, fidelity to their interactions, and scope to the phenom-
ena explored. The extraordinary advances in single-scale manipulation, in vivo
cellular and molecular imaging, and of course, computational speed, memory,
and software for distributed computing together promise that this effort will
