Tissue Development, Repair, and Remodeling - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 727

11.6.1 Plasma Enzymatic Systems

Four interconnected plasma enzymatic systems produce mediators: (1) kinins,
(2) complement, (3) coagulation factors, and (4) components of the fibrinolytic
system. Tissue damage activates clotting factor-XII, which triggers the kinin and
clotting cascades.
Bradykinin causes vasodilation and increased permeability. Cell-bound
bradykinin also promotes histamine production. The fibrinolytic system leads to
plasmin synthesis. Plasmin degrades the fibrin clot and activates the complement
system.

11.6.2 Involved Cells

Many cell types are involved: (1) platelets (Table 11.13 ); (2) immunocytes (den-
dritic cells, lymphocytes, monocytes, and neutrophils); (3) vascular cells such as
endothelial cells, and (4) tissue cells, such as fibroblasts and keratinocytes in the
case of skin wound. 65 Nucleated cells change their gene expression to proliferate,
differentiate, and migrate. Repair begins with a scar that mainly contains fibroblasts
and extracellular matrix predominantly made of collagens. Tissue remodeling and
regeneration is ensured by stem cells. 66

65 Wound re-epithelialization involves many growth factors: fibroblast growth factors FGF7 and
FGF10 that bind to FGFR2-3b receptor; hepatocyte growth factor that targets HGFR receptor;
and transforming growth factor- and heparin-binding epidermal growth factor-like growth factor

that associates with epidermal growth factor receptor [ 1473 ]. Activated receptors trigger signaling
via signal transducer and activator of transcription STAT3 and AP1 proteins. Whereas TGF β
impedes wound re-epithelialization via transcriptional regulator SMAD3, activin that also signals
via SMAD3, promotes keratinocyte proliferation in the wound site. In addition, acetylcholine and
its receptors synthesized by keratinocytes in an autocrine loop either stimulate or hamper migra-
tion via muscarinic acetylcholine muscarinic M 3 and M 4 receptors, respectively. Keratinocytes
also produce catecholamines and their receptors that inhibit re-epithelialization in an autocrine
manner. Polyunsaturated fatty acids and derivatives that activate peroxisome-proliferator-activated
receptors PPAR

α

α and PPAR β in keratinocytes after skin injury also regulate re-epithelialization.

Factor PPAR is also upregulated by pro-inflammatory cytokines via AP1 proteins and the

stress-activated protein-kinase cascade. Factor PPAR

β

enhances cell survival by upregulating the
expression of integrin-linked kinase (ILK) and 3-phosphoinositide-dependent protein kinase PDK1
that phosphorylate (activate) anti-apoptotic PKB.
66 Epidermis permanently and rapidly renews itself owing to epidermal stem cells. The upper region
of hair follicle below the sebaceous glands contains multipotent progenitor cells.

β