Connective Tissue Flashcards
5 types of CT
Areolar tissue
Adipose
White fibrous
Yellow elastic
Reticular
Homeostasis in wound healing
Establishes the fibrin provisional wound matrix and platelets, provide initial release of cytokines and growth factors in the wound
Inflammation in wound healing
Mediated by neutrophils and macrophages
Removes bacteria and denatured matrix components
Source of growth factors and cytokines
Prolonged elevated inflammation => retards healing due to high levels of proteases and reactive oxygen that destroys essential factors
Proliferation in wound healing
Fibroblasts supported by new capillaries, proliferate and synthesise disorganised ECM
Basal epithelial cells proliferate and migrate over the granulation tissue to close the wound surface
Remodelling in wound healing
Fibroblasts and capillary density decreases and initial scar tissue is removed and replaced by ECM that is more similar to normal skin
Result of balanced regulated activity of proteinases
Tissue regeneration
Remaining cells of an injured organ regrow to offset the missed cells
Cornerstone of tissue engineering leading to NEW growth
Embryonic wound healing
Early gestation foetus can heal wounds without scar
Foetal dermis -> regenerate non-disrupted collagen matrix -> identical to original tissue
Foetal collagen Vs post-natal collagen Vs adult collagen
Foetal:
Type III collagen rapidly deposited => fine reticular network => indistinguishable
Post-natal:
Ratio of type I to type III increases => more strength and rigidity => may impeded cellular migration and regeneration
Adult:
Collagen synthesis delayed while fibroblasts proliferate
Hyaluronic acid
Net negative charge traps and impede water molecules which allows resistance to deformation and facilitates cellular movement
Hyaluronic acid in foetal wound healing
More Hyaluronic acid => more HA receptors
In scarless foetalwounds => HA increased more rapidly than adult
Less pro inflammatory cytokines such as IL-1 and TNFalpha that downregulate HA expression
Adhesion proteins in foetal wounds
Enhanced ability to upregulate tenascin and fibronectin which mediate ECM attachment and attract fribroblasts, keratinocytes and endothelial cells to site of injury
=> rapid deposition of an organised matrix => less scarring
Inflammatory cells in foetal wound healing
Immune system not fully developed
Embryo is undergoing rapid growth and differentiation
Role of TGFbeta in wound healing
Inflammation
Stimulatory angiogenesis
Fibroblast proliferation
Collagen synthesis and deposition
Remodelling of the new ECM
Foetal platelets produce less PDGF, TGF-B1 and TGF-B2
TGF beta in foetal wound healing
High levels of TGFbeta3 from keratinocytes and fibroblasts
Low levels of TGFbeta1 and TGFbeta2
High levels of fibroblast growth factor
PDGF not detected
IL6 in wound healing
Stimulates monocyte chemotaxis and macrophage activation
IL8 in wound healing
Attracts neutrophils and stimulates neovascularisation
Interleukin expression in wound healing Adult Vs Foetal
Adult:
Elevation in IL6 and IL8 up to 72 hours
Foetal:
IL6 and IL8 elevation not present after 12 hours
Significantly lower expression
Addition of IL6 to foetal wounds produces a scar in normally scarless wounds
How do we detect EMT?
Loss of surfactant production
Gain of ECM or metalloproteinase secretion
Differences in N and E Cadherin
Differences in cytoskeletal proteins e.g. loss of cytokeratins,gain of vimentin
Type 1 EMT
Tissue and organ formation during embryogenesis
Type 2 EMT
Normal wound healing, tissue regeneration and fibrosis, and plays a role in excessive tissue repair
Associated with inflammation; normally terminated once repair is completed
In organ fibrosis type 2 EMT can continue to respond to ongoing inflammation => organ destruction
Type 3 EMT
Indicates acquisition of migratory phenotype by malignant epithelial cells associated with tumour invasiveness and metastasis
Fibrosis
Thickening and scarring of CT usually as result of injury
Excess accumulation of ECM components
Drives end-stage organ failure
Idiopathic pulmonary fibrosis
Disease of the lung; parenchymal scarring; death
Inability of alveolar epithelium to regenerate after injury
Type 1 alveolar cells
Provide thin walled gas exchange surface
Type 2 alveolar cells
Functions as stem cells, contributing to alveolar renewal and repair
-facultative progenitor cells (not always functional)
-favouring of excessive ECM deposition and fibrosis
Myofibroblasts in IPF
Origin is controversial
ATII cells that have undergone EMT may be source
Critical in pathogenesis of IPF
IPF modulated by:
Repetitive injury
Inefficiency of ATII cells => abnormal repair and failure of alveolar regeneration
Aberrant pathway activation
IPF 7 keys factors at play
Aberrant activation of:
[1] Wnt/B-catenin
[2] Sonic hedgehog
[3] TGF-Beta and other developmental pathways
[4] ZEB transcription factors initiated by extracellular ligand binding
=> downregulation of [5] E Cadherin expression in epithelial cells
Profibrotic environment created in which collagen-producing [6]fibroblasts and myofibroblasts accumulate through different mechanisms such as proliferation and differentiation of resident lung fibroblast
[7] cell environment e.g. ROS
______ master switch in induction of fibrosis.
TGFbeta
Inability to respond to ________ affords protection from bleomycin-induced fibrosis
TGFbeta1
TGFbeta-SMAD dependent canonical pathway
TGFbeta binds receptor and promotes SMAD 2/3 phosphorylation
Active SMAD 2/3 forms complex with SMAD4
Complex binds to promoter region of target genes ass. With EMT
HSP90 is suggested to contribute in both canonical and non-canonical TGFbeta signalling pathways in IPF
TGFbeta independent non-canonical pathway
Transduce through Ras-MAPK and P13K-Akt
Role for ubiquitin-proteasome pathway
- Skp2 and Fbw7 are E3 ubiquitin ligases
- Skp2 promotes p27 degradation
- Fbw7 promotes telomere protection protein 1 degradation
P27 is a kinase inhibitor and acts as a cell cycle inhibitor
TPP1 acts to protect chromosomes
Wnt signalling in EMT
TGFbeta stim canonical Wnt in a p38 dependent manner by decreasing expression of endogenous Wnt aganosit Dickkopf-1 -> Wnt binds Fed, inducing its phosphorylation -> cytosolic beta-catenin accumulation -> translocated to nucleus -> interacts with transcription factors => EMT
SMAD co-activator
Beta catenin
Other pathways involved in EMT(4)
Wnt
Delta-notch
NFkB
Shh
