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Page 4 of 18 Rodriguez. Plast Aesthet Res 2023;10:67 https://dx.doi.org/10.20517/2347-9264.2023.73

including cytoplasmic and chromatid changes. For a schematic illustration of these experiments, see
Figure 2.

This suggests that damaged cells were sending messages to adjacent cells that were, in turn, causing damage
to these “bystander” non-irradiated cells. This is a phenomenon well known in immunology, where
damaged cells release either damaged portions of the cell structure or specific biochemical signals that alert
other cells to the damage. Some of these are called DAMPS or damage associated molecular pattern
molecules . Many DAMPs are nuclear or cytosolic proteins. When released outside the cell or exposed on
[12]
the surface of the cell following tissue injury, they move from a reducing to an oxidizing milieu, which
results in their denaturation. Others are direct products of energy transfer (ROS-reactive oxygen species).
[3]
These compounds act as an alarm signal to the immune system. They create a “sense of danger” in the
tissues that results in an organized response by the tissue.

Because of these findings, the focus on countering the iatrogenic effects of radiation therapy has expanded
from dosage delivery strategies to an effort to understand how the body responds to the radiation injury.
The objective is to support and leverage the body’s hemostatic response mechanisms.

Figure 3 illustrates the concept of cell damage in the “target cell theory” versus the concept of “RIBE”. In
this diagram, the effect of irradiation on the matrix is also added. As we will discuss later, the release of
cytokines in the matrix, specifically TGF-β, plays a major role in RIF.

TISSUE RESPONSE PATTERNS- INFLAMMATION, REGENERATION, REMODELING
The body’s homeostatic response patterns to injury are well known to surgeons as “The wound healing
curves”. Under normal circumstances, the three phases of healing (inflammation, regeneration, and
remodeling) each have their own set of triggering signals, messenger cytokines, as well as effectors and
target cells, and temporal and spatial cues . Each phase follows a common pattern, which is broadly
[13]
divided into steps [Figure 4].

Step 1- For example, in the inflammatory pathway, the danger signals can be TNF-α (tumor necrosis factor),
DAMPS (in the case of ARS), or PAMPS (pathogen associated molecular pattern molecules) in the case of
infection. Step 2-These signals are picked up by the TLRs (toll-like receptors) embedded in the macrophage
(M1 inflammatory type) cell wall. Step 3-The macrophage then acts as an amplifier of the signal by secreting
inflammatory cytokines such as IL-6 (interleukin) that activate lymphocytes and activating other immune
defense cells. Step 4- These immune effector cells (T lymphocytes, B lymphocytes) are the ones that attack
pathogens or host bystander tissue. Step 5- Depending on local conditions, the effector cells send feedback
to the sentinel cells to mitigate the amplification response (negative feedback loop) or accelerate it (positive
feedback loop). They may also alter or reprogram host tissue cell function.

In penetrating or blunt trauma, a multitude of danger signals are released in a gradient over space and time.
Sentinel cells react to these various signals in different ways. Consequently, a cascade of different tissue
responses triggered over time results in an orderly progression from inflammation to regeneration and
finally tissue remodeling.

Ideally, after the mitigation of the inflammatory reaction, the regenerative response takes over. Some of the
signals for the regenerative response are the same “danger signals” and amplified cytokines from the
inflammatory response. The regenerative response shares a proliferative function with the inflammatory
reaction, but also carries with it an immune modulatory function that acts as a counterweight to the