Repair of Cell Injury Flashcards
What is the definition of healing?
A response to tissue injury, and represents an attempt by the organism to restore integrity to an injured tissue
- overlaps the inflammatory process
- induction of an acute inflamm response
What happens if the injury results in destruction of epithelium ONLY?
This is an erosion; heals exclusively by regeneration of parenchymal cells
What happens if the injury results in destruction of the basement membrane (extracellular matrix)?
A scar will form (“healing”)
What 2 processes does repair occur by?
- Complete regeneration: replacement of dead cells (tissue) by proliferation of parenchymal cells of same type (return to normal state)
- Incomplete regeneration/healing: replacement by connective (fibrous) tissue -> permanent scar formation
What are the 3 groups of cells of regenerative capacity?
- Labile cell - constantly proliferating
- Stable cell - quiescent, minimal replicative activity
- Permanent cell - terminally differentiated, nonproliferative
What cells constitute the labile cells?
Epithelium of skin, respiratory tract, GI tract, urinary tract, lymphoid cell, bone marrow, vagina, cervix, bladder
What cells constitute the stable cells?
Parenchymal cells in liver, alveolar cells of lung, epithelium of kidney, pancreas, salivary gland
What cells constitute the permanent cells?
Myocardium, skeletal muscle, neuron
What are the cell cycle phases?
- G1 phase = presynthetic
- S phase = DNA synthesis
- G2 phase = premitotic
- M phase = mitotis
- G0 phase = nonproliferative (growth arrest)
At what phase can cells leave the cell cycle and then either cease proliferation, differentiate, or eventually be recruited back to the cycle?
G1 phase
At what phase are the continuously cycling labile cells?
S phase
- remain in the cell cycle at all times
- can easily regenerate after injury
- contain a pool of stem cells
At what phase are the quiescent, stable cells?
G0 but can be recruited back into G1
At what phase are the permanent cells?
G0
- cells cannot undergo mitotic division
- cells stop multiplication early in neonatal life
Fill in chart
- Complete regeneration
- Fibrous repair
- Complete regeneration
- Fibrous repair
- Fibrous repair
- Fibrous repair
What regulates the mechanisms involved in repair?
- Growth factors
- Extracellular matrix synthesis and collagenization
- Cell-to-cell and cell-to-matrix interactions
What proteins stimulate the survival and proliferation of particular cells by binding to a specific receptor on the target cell?
Growth factors
Which growth factor is a polypeptide present in saliva, milk, urine, plasma, and macrophages?
Epidermal Growth Factor (EGF)
What function does EGF have?
Mitogenic for a variety of epithelial cells:
- Acts on keratinocytes -> migrate/divide
- Acts on fibroblasts -> produce “granulation” tissue, synthesize ECM/collagen
Which growth factor is primarily found in the alpha granules of platelets and is released subsequent to platelet activation?
Platelet-derived Growth Factor (PDGF)
- Also produced by activated macrophages, endothelium, and smooth muscles
What functions do PDGF have?
- Causes proliferation/migration of fibroblasts, smooth muscle cells, and monocytes
- Chemotactic for MANY cells
- Another KEY player in formation of granulation tissue
Which growth factor stimulates fibroblast proliferation and angiogenesis (neovascularization)?
Fibroblast Growth Factor (FGF)
What does neovascularization involve?
Enzymatic degradation of the basement membrane of the parent vessel -> migration of endothelial cells toward the angiogenic stimulus -> proliferation of endothelial cells -> maturation of endothelial cells -> organization into capillary tubes
Which cells produce Tumor Necrosis Factor (TNF)?
- Macrophages
- Mast cells
- CD4 lymphocytes
- NK cells
- T lymphocytes
What functions does TNF have?
- Stimulates fibroblastic proliferation
- Stimulates synthesis of collagen
- Stimulates phagocytosis, chemoattractant for neutrophils
- Promotes expression of adhesion molecules on endothelial cells - helps neutrophils migrate
- Promotes fever
- Promotes lipid/protein mobilization and suppresses appetite
- Weight loss/anorexia
- TNF antagonists effective for chronic inflamm disease (RA)
What cells produce Interleukin 1 (IL-1)?
- Macrophages
- Monocytes
- Fibroblasts
- Dendritic cells
What functions does IL-1 have?
Increases expression of adhesion factors on endothelial cells to enable transmigration of immunocompetent cells (such as phagocytes, lymphocytes, and others) to sites of infx
- similar to TNF, greater role in fever
What cells produce IL-6? What is its principal action in acute inflamm?
- Source: Macrophages, other cells
- Action: Systemic effects (acute phase response)
What cells produce chemokines? What are there principal actions in acute inflamm?
- Source: Macrophages, endothelial cells, T-lymphocytes, mast cells
- Action: Recruitment of leukocytes to sites of inflamm; migration of cells in normal tissues
What cells produce IL-17? What are its principal actions in acute inflamm?
- Source: T lymphocytes
- Action: Recruitment of neutrophils and monocytes
What cells produce IL-12? What are its principal actions in chronic inflamm?
- Source: Dendritic cells, macrophages
- Action: Increased production of IFN-gamma
What cells produce IFN-gamma? What are its principal actions in chronic inflamm?
- Source: T lymphocytes, NK cells
- Action: Activation of macrophages (increased ability to kill microbes and tumor cells)
What cells produce IL-17? What are its principal actions in chronic inflamm?
- Source: T lymphocytes
- Action: Recruitment of neutrophils and monocytes
In what ways has research found that fever aids healing?
- Increased leukocyte mobility
- Decreased effect of endotoxins
- Increased proliferation of T cells
- Increased phagocytosis
What is the role of the extracellular matrix (ECM) in tissue repair?
- Mechanical support for cell anchorage
- Determination of cell orientation (polarity)
- Control cell growth
- Maintenance of cell differentation
- Scaffolding for tissue renewal
- Establishment of tissue microenvironments, storage/presentation of regulatory molecules
What is the ECM? What 2 forms does it exist as?
A dynamic, constantly, remodeling, macromolecular complex
- Interstitial matrix
- Basement membrane (BM)
What are major components of the ECM?
- Collagens
- Elastic fibers
- Fibronectin
- Laminin
- Proteoglycans
What fibrous structural protein makes up 25-30% of protein in mammals?
Collagen
What is the basic unit of collagen?
Tropocollagen (3 alpha chains)
What happens during the intracellular synthesis of collagen?
Synthesis of polypeptide chains -> PROCOLLAGEN (has disulfide bonding, triple helix)
What happens during the extracellular synthesis of collagen?
Cleavage of procollagen -> TROPOCOLLAGEN -> oxidation of lysine results in cross-linking of alpha chains of adjacent molecules (provides tensile strength) -> COLLAGEN FIBRIL
Where is type 1 collagen distributed?
Dermis, scar, bone, tendon
- bundles, high tensile strength
Where is type II collagen distributed?
Cartilage, vitreous humor
- structural protein
Where is type III collagen distributed?
Liver, blood vessels
- Pliable
Where is type IV collagen distributed?
All basement membranes
- Amorphous
What is the basic unit of elastic fibers?
Tropoelastin
How are elastin polypeptide chains bound?
Covalently bound by desmosine linkages
What is the most abundant glycoprotein in basement membrane?
Laminin
- Connects cells to underlying ECM components (i.e. type IV collagen and heparan sulfate)
Which component of the ECM permits resilience and lubrication?
Proteoglycans (highly glycosylated proteins)
What does the basic proteoglycan unit consist of?
A “core protein” w/ one or more covalently attached glycosaminoglycan (GAG) chain(s)
What are the functions of proteoglycans?
- Binding/packing of tissues (CT proper)
- Connect, anchor, and support body and its organs
- Transport of metabolites between capillaries/tissues
- Filler, keeps ECM “fluid” allowing for resistance to compressive forces
What cell-to-cell interactions exist that control the density-dependent regulation (to cease cell proliferation)?
- Limitation of necessary materials in the envir
- Alterations in the number of receptor sites for GFs
- Accumulation of growth inhibitors
What cell-to-matrix-interactions exist that influence cell proliferation/differentiation?
- Type of collagen
- Presence of fibronectin/laminin
- Nature of proteoglycans
What field of medicine does stem cell research stand at the core of?
Regenerative medicine
What are stem cells characterized by?
Their prolonged self-renewal capacity and by their asymmetric replication (in every cell division, one of the cells retain its self-renewing capacity while other enters a differentiation pathway and is converted to a mature, non-dividing population)
What are the 2 types of stem cells discussed?
- Embryonic stem cells (ESC)
- Most undifferentiated
- Adult stem cell (ASC)
- Bone marrow
- Tissue
Which group of stem cells have been used to study the specific signals and differentiation steps required for development of many tissues?
ES cells
- Production of knockout mice
- In the future may be used to repopulate damaged organs
What are the steps involed in therapeutic cloning, using ES cells for cell therapy?
- Diploid nucleus of an adult cell from a pt. is introduced into an enucleated oocyte
- Oocyte is activated -> zygote divides -> blastocyst (contains donor DNA)
- Blastocyst is dissociated to obtain ES (these cells are capable of differentiating into various tissues)
If tissue injury is severe or chronic or results in destruction of parenchymal cells or stromal framework, what kind of repair happens?
Incomplete repair by unregenerated parenchymal cells w/ fibrosis
What are the 4 components of fibrosis (repair by CT)?
- Angiogenesis
- Migration and proliferation of fibroblasts
- Deposition of ECM
- Remodeling (maturation/reorganization of fibrous tissue)
What process is critical in healing at sites of injury, in development of collateral circulations at sites of ischemia, and in allowing tumors to increase in size beyond constraints of their original blood suppy?
Angiogenesis
What are the 4 steps of angiogenesis?
- Proteolytic degradation of parent vessel BM -> formation of a capillary sprout
- Migration of endothelial cells from original capillary toward an angiogenetic stimulus
- Proliferation of endothelial cells behind the leading edge of migrating cells
- Maturation of endothelial cells w/ inhibition of growth and organization into capillary tubes
What is the initial event in the repair of an injury that consists of richly vascular CT which contains newly formed blood vessels (capillaries), young fibroblasts, and a variable infiltrate of inflamm cells (macrophages)?
Granulation tissue
***do NOT confuse w/ granuloma
How many days after injury does granulation tissue form?
By day 3-5
- Soft, pink, granular tissue
- Progressively changes/matures into dense fibrous tissue & scar formation
What are the roles of granulation tissue in fibrous repair?
- Growth into necrotic tissue, hemorrhage, thrombi, inflamm exudate and replace them (organization)
- Connect the separated tissue, restore the lost tissue and support them to keep the integrity of body
- Protect the wound and anti-infx
What is contraction during wound healing?
Accounts for a reduction in size of the defect
- Produces faster healing (only 1/3 - 1/2 of original defect must be repaired)
What cells account for contraction?
Myofibroblasts (intermediate type of cell - between a fibroblast and a myocyte)
What does it mean to heal by primary intention?
A clean wound w/ well-apposed edges, and minimal clot formation
- Usual case w/ a surgical wound
- Epithelial repair = mechanism of repair
- Sutures, staples, tape, etc.
What happens within 24 hours of healing by primary intention?
- Neutrophils appear at edges of incision, migrating toward fibrin clot
- Epithelial cells from both edges migrating/proliferating along dermis -> deposit basement membrane components
- Cells meet in midline under surface scab -> thin, continuous epithelial layer
What happens within 72 hours of healing by primary intention?
- Macrophages are usually most numerous inflamm. cells
- Granulation tissue starts to develop
- Collagen fibers present but do not bridge incision site
- Epithelial cells continue to proliferate under scab and epidermal covering over incision thickens
What happens by day 5 of healing by primary intention?
- Incision space filled w/ granulation tissue
- Collagen fibers begin to bridge incision
- Epidermis returns to its normal thickness and keratinized architecture
What happens during the 2nd week of healing by primary intention?
- Continued accumulatin of collagen fibers + proliferation of fibroblasts
- Inflamm cells and edema disappear
- Blanching
What is blanching?
Process whereby collagen fibers accumulate and excessive vascular channels regress -> area becomes light in color
- happens during 2nd week of healing by 1’ intention
What happens by the end of 1 month of healing by primary intention?
- CT scar that is devoid of inflamm cells + covered by an intact epidermis
- Damaged adnexal structure are permanently lost
- Tensile strength still well below max
Which type of healing is used in larger infected contamined wounds?
Healing by second intention
What does it mean to heal by secondary intention?
When wound edges cannot be apposed (e.g., following wound infx), then the wound slowly fills w/ granulation tissue from bottom up
How does secondary union differ from primary?
- Large tissue loss w/ large defect -> large blood clot/scab formed, require more time to close
- Involves combo of regeneration + scarring (fibrosis predominates)
- More inflamm
- More granulation tissue formation -> hypertrophic scar
- Wound contraction/contracture of myofibroblasts -> limitation of joint movements
What are some factors that influence wound healing?
- Type/size/location of wound
- Infection (delays wound healing -> more gran tissue/scarring)
- Movement (wounds over joints don’t heal well b/c traction)
- Radiation
- Vascular supply
- Overall nutrition
- Age (younger is better)
- Hormones
How does radiation affect wound healing?
Ionizing radiation inhibits proliferation (e.g. radiotherapy for malignant tumor is delayed until surgical scar has been healed)
How does vascular supply affect wound healing?
- Local venous obstruction
- DM will delay healing of pretibial skin wounds
How does overall nutrition influence wound healing?
Vitamin and protein deficiencies -> poor wound healing
- Especially vitamin C + Zinc (involved in collage synthesis)
- Protein - calorie malnutrition
How do hormones influence wound healing?
Corticosteoids drastically impair wound healing b/c of profound effect on inflamm cells
What are some complications of wound healing?
- Defective scar formation (dehiscence)
- Excessive scar formation (keloid)
- Contraction
What is dehiscence or ulceration usually due to?
- Wound infx (common)
- Malnutrition (scurvy - rare)
- Hypoxia w/ ulceration, usually due to inadequate vascularity in a skin flap (common)
Why does a scar become softer, smaller after surgical operation or trauma?
B/c of degradation of collagens and other elements of ECM by metalloproteinases (collagenases)
What is a keloid?
Overgrowth of scar (hypertrophic scar)
- Result of over-exuberant production of scar tissue (primarily composed of type III collagen)
- Cause may be genetic (lack of proper metalloproteinases to degrade type III collagen)
What is contracture?
Excessive contraction of a wound
- Special problem in tx of extensive burns
- Affects several diseases of unknown cause (peyronie disease of the penis)
How is the process of healing in heart tissue different?
Cardiac myocytes are permanent cells; don’t divide -> collagenous scar tissue formation
What are the steps in bone healing?
- Inflamm (formation of fx hematoma)
- Soft callus formation (cell division + growth of new blood vessels)
- Chrondocytes secrete collagen + proteoglycans -> fibrocartilage
- Hard callus formation (endochondral ossification + direct bone formation -> woven bone)
- Remodeling
Why is bone the only tissue to heal without a scar?
B/c it’s constantly remodeled (highly organized cortical bone replaces weaker, disorganized woven bone)
What type of healing will occur in these exs: liver regeneration after partial hepatectomy, superficial skin wounds, resorption of exudate in lobar pneumonia?
Regeneration
What type of healing will occur in these exs: deep excision wounds, MI?
Healing/scar formation
What type of healing will occur in these exs: chronic inflamm diseases (cirrhosis, chronic pancreatitis, pulmonary fibrosis)?
Fibrosis
