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Rodriguez. Plast Aesthet Res 2023;10:67 https://dx.doi.org/10.20517/2347-9264.2023.73 Page 7 of 18

TGF-β belongs to one of the major groups of cytokines (same family as BMP) and is important in
[20]
embryonic axial development . In the limbs, for example, it directs embryonic cells down terminal
differentiation pathways along axial gradients as well as selective apoptosis; for example, it is responsible for
the apoptosis and disappearance of the web membrane between the fingers.

In the adult, TGF-β is one of the dominant cytokines in the tissue remodeling phase.

Characteristics that make TGF-β a likely candidate for generating a “cytokine storm” are:

(A) TGF-β and its receptor are both manufactured by all cell types. Inside the cell, TGF-β is coupled to a
ligand (LTBP- Latent TGF-β Binding Protein) and secreted to the extracellular space as an inert complex
“L-TGF-β” (latent TGF-β).

(B) L-TGF-β is abundantly distributed throughout the extracellular space as a “matrikine” or cytokine that is
embedded in the tissue matrix.

(C) The TGF-β/Receptor complex is “sticky”, i.e., it stays bound for a period while intracellular messengers
(SMAD 3,4) shuttle between the cell membrane and nucleus.

(D) Thus, every cell can be affected by and act as an amplification agent for TGF-β.

As a result of TGF-R stimulation, a suite of gene products are transcribed that activate a suite of intracellular
pathways that culminate in altered cell behaviors . These are:
[21]

● Differentiation of epithelial and mesangial cell lines to fibroblast and myofibroblast lineage.

● Directed cell senescence.

● Stimulation of apoptosis.

● Epithelial and endothelial mesenchymal transition (EMT and EnMT).

● Stimulation of collagen deposition.

● Stimulation of TIMPS (temporary inhibitors of metalloproteinases).

● Downregulation of metalloproteinases.

How radiation damage differs from other types of trauma
In most types of trauma, such as blunt or penetrating trauma, a variety of “danger signals” (DAMPS,
cytokines TNF-alpha, IFN, etc.) are released in a concentration gradient and a temporal sequence. In the
case of RIF specifically, contact with ROS (reactive oxygen species) created by irradiation uncouples the L-
[22]
TGF-β complex in the matrix of the entire irradiated field and releases the active TGF-β . Because TGF-β is
abundant and ubiquitous in the matrix, the TGF-β predominates in a uniform distribution over the entire
irradiated area [Figure 5]. The activated TGF-β then binds to its cell membrane receptor (TGFR) in adjacent
cells. It is as if the “normal” inflammatory danger signals and sentinel cell steps are paralleled by a pervasive,