Exam III: Inflammation Part III Flashcards
Acute Phase Response
Associated with cytokine-induced systemic reactions
Example: severe bout of a viral illness (influenza)
Cytokines (stimulated by bacterial products such as LPS)
TNF, IL-1, and IL-6 are important mediators of the acute-phase reaction
Type I interferons (also contribute)
Acute Phase Response: Clinical and Pathology Changes
- Fever from pyrogens
- Prostaglandins that increase in body temperature
Produced in the vascular and perivascular cells of the hypothalamus
Exogenous pyrogens stimulate leukocytes to release cytokines (endogenous pyrogens)
Increase the enzymes (cyclooxygenases) that convert AA into prostaglandins
In hypothalamus….PGE2 stimulates the production of neurotransmitters that reset temp set point higher
Acute Phase Proteins
Plasma proteins (liver) Plasma concentrations may increase several hundred-fold
Types of proteins: C-reactive protein (CRP), Fibrinogen, and Serum amyloid A (SAA) protein
Many acute-phase proteins (CRP and SAA)
Bind to microbial cell walls—may act as opsonins and fix complement
Bind chromatin—possibly aiding in clearing necrotic cell nuclei
Fibrinogen
Fibrinogen
Binds to red cells
Forms stacks (rouleaux)
Sediment more rapidly at unit gravity than do individual red cells
Increased erythrocyte sedimentation rate
Hepcidin
Production is increased
Iron-regulating peptide
Chronically elevated plasma concentrations reduce availability of iron
Responsible for theanemia associated with chronic inflammation
Acute Phase Response: Repair
Injury to cells—series of damaging events—initiation of healing process
Regeneration: complete restitution of lost or damaged tissue
Repair: may restore some original structures, but can cause structural derangements
Healthy tissues
Healing (regeneration/repair): occurs after any insult that causes tissue destruction and essential for the survival of the organism
Repair of Superficial and Severe Injury
Normal epidermis- see a couple lymphocytes and macrophages just waiting
Superficial injury: just a small layer of tissue is damaged
Severe Injury: epidermis and dermis damaged (deeper) injury that causes bleeding = scar tissue
Regeneration: General Information
Proliferation of cells and tissues to replace lost structures
Growth of an amputated limb in amphibians
Mammalian whole organs and complex tissues rarely regenerate after injury
Applied to liver growth after partial resection or necrosis
Compensatory growth rather than true regeneration
Regeneration: Hematopoietic System, Skin, and GI Tract
Hematopoietic system, skin, GI tract
High proliferative capacity
Renew themselves continuously
Regenerate after injury
Regeneration in the liver, somewhat in the kidney, and in the skin
Hemeopoietic system: regenerates from bone marrow
GI tract: when you eat, as the food goes down it takes cells with it and those cells are replaced
Repair
Combination of regeneration and scar formation
Deposition of collagen
Contribution of regeneration and scarring:
Ability of the tissue to regenerate
Extent of the injury
Example: superficial skin wound heals through the regeneration of the surface epithelium
Regeneration vs. Repair
Regeneration = fixes with the same cell type
Repair: fixes with a different type of cell like collagen
Injury to ECM and Cells
Injury to hepatocytes = regeneration of the liver = functional tissue
If the cells and ECM are injured, there is no structure whatsoever so the cells will not regenerate properly in a nice pattern like before because no scaffolding for cells = non-functional tissue
Repair of Chronic Inflammation
Accompanies persistent injury
Stimulates scar formation
Local production of growth factors and cytokines
Promote fibroblast proliferation and collagen synthesis
Fibrosis
Extensive deposition of collagen: starts as loose deposit, then over time becomes hardened
Extracellular matrix (ECM): components are essential for wound healing because it provides the framework for cell migration
Maintain the correct cell polarity for the re-assembly of multilayer structures
Participate in angiogenesis (formation of new blood vessels)
ECM: fibroblasts, macrophages, and others produce growth factors, cytokines, and chemokines critical for regeneration and repair
Normal Cell Proliferation
Adult tissues
Size of cell populations determined by rate of cell proliferation, differentiation, and death
Increased cell numbers may result in increased proliferation and decreased cell death
Apoptosis: physiologic process required for tissue homeostasis induced by a variety of pathologic stimuli
Terminally Differentiated Cells
Differentiated cells incapable of replication
Impact of differentiation
Depends on the tissue under which it occurs
Differentiated cells are not replaced
Differentiated cells die but are continuously replaced by new cells generated from stem cells
Physiologic Proliferation
Proliferation of endometrial cells under estrogen stimulation during the menstrual cycle
Thyroid-stimulating hormone-mediated replication of cells of the thyroid that enlarges the gland
Stimuli may become excessive, creating pathologic conditions
Pathologic Proliferation
Nodular prostatic hyperplasia
Dihydrotestosterone stimulation= BPH
Nodular goiters in the thyroid
Increased serum levels of thyroid-stimulating hormone
3 Types of Tissues Within the Body
Basis of the proliferative activity of their cells
- Labile tissues (Continuously dividing)
- Stable tissues (Quiescent)
- Permanent tissues (Nondividing)
Labile Tissues
Cells proliferate throughout life aka continuous
Replaces destroyed cells
Surface epithelia: stratified squamous epithelia of the skin, oral cavity, vagina, and cervix, lining mucosa of all the excretory ducts of the glands of the body
Salivary glands, pancreas, biliary tract
Columnar epithelium of the GI tract and uterus
Transitional epithelium of the urinary tract
Cells of the bone marrow and hematopoietic tissues
Mature cells are derived from adult stem cells, which have a tremendous capacity to proliferate
Quiescent Tissues
Low level of replication
Cells from these tissues undergo rapid division in response to stimuli
Capable of reconstituting the tissue of origin
Parenchymal cells of liver, kidneys, and pancreas
Mesenchymal cells: fibroblasts and smooth muscle
Vascular endothelial cells
Lymphocytes and other leukocytes
Example: ability of liver to regenerate, partial hepatectomy or acute chemical injury
Quiescent Tissue Cell Types
Fibroblasts, endothelial cells, smooth muscle cells, chondrocytes, and osteocytes
Quiescent in adult mammals
Proliferate in response to injury
Fibroblasts proliferate extensively
Non-Dividing Tissues
Contain cells that have left the cell cycle
Cannot undergo mitotic division in postnatal life
Neurons
Skeletal muscle cells
Cardiac muscle cells
Neurons in the central nervous system (CNS): destruction of cells are replaced by the proliferation of the CNS-supportive elements like glial cells
Mature Skeletal Muscle and Cardiac Muscle: Repair
Nondividing tissues
Mature skeletal muscle: cells do not divide
Regenerative capacity through the differentiation of the satellite cells attached to the endomysial sheaths
Cardiac muscle: very limited regenerative capacity
Large injury to the heart muscle like myocardial infarction followed by scar formation
Stem Cells
Characterized by: self-renewal properties and capacity to generate differentiated cell lineages
Need to be maintained during the life of the organism
Achieved by two mechanisms:
1. Obligatory asymmetric replication: with each stem cell division, one of the daughter cells retains its self-renewing capacity while the other enters a differentiation pathway
2. Stochastic differentiation: stem cell population maintained by the balance between stem cell divisions that generate either two self-renewing stem cells or two cells that will differentiate
Locations of Stem Cells
Bone marrow Skin Gut Liver Brain Muscle Cornea
Bone Marrow
Contains hematopoietic stem cells (HSCs)
Contains stromal cells aka multipotent stromal cells, mesenchymal stem cells or MSCs
Hematopoietic Stem Cells: generate all of the blood cell lineages, reconstitute the bone marrow after depletion caused by disease or irradiation
Hematopoietic Stem Cells
Widely used for the treatment of hematologic diseases
Collected directly from:
Bone marrow
Umbilical cord blood
Peripheral blood of individuals receiving cytokines: granulocyte-macrophage colony-stimulating factor, which mobilize HSCs; make the person have a fever and sick because the body is trying to produce all the cells to donate to someone else
Marrow Stromal Cells (MSCs)
Multipotent
Potentially important therapeutic applications: generate chondrocytes, osteoblasts, adipocytes, myoblasts, and endothelial cell precursors
Depends on the tissue to which they migrate
Migrate to injured tissues
Generate stromal cells or other cell lineages
Do not participate in normal tissue homeostasis
Liver Regeneration
Contains stem cells/progenitor cells in the canals of Hering: junction between the biliary ductular system and parenchymal hepatocytes
Give rise to a population of precursor cells: oval cells, which are bipotential progenitors capable of differentiating into hepatocytes and biliary cells
Oval Cells
Cells of the liver
Function as a secondary or reserve compartment, which are activated only when hepatocyte proliferation is blocked
Proliferation and differentiation during fulminant (sudden onset) hepatic failure, liver tumorigenesis, and chronic hepatitis and advanced liver cirrhosis
Brain Regeneration
Neurogenesis from neural stem cells (NSCs)
Occurs in the brain of adult rodents and humans
AKA neural precursor cells
Capable of generating neurons, astrocytes, and oligodendrocytes
Identified in two areas of adult brains:
Subventricular zone (SVZ)
Dentate gyrus of the hippocampus
Compensatory Growth
Even this process is not one of true regeneration
Resection of tissue does not cause new growth of liver
Triggers a process of compensatory hyperplasia in the remaining parts of the organ
Other organs capable of compensatory growth
Kidney, pancreas, adrenal glands, thyroid, and the lungs of very young animals
Display it in less dramatic form than the liver
Kidney Regeneration
New nephrons cannot be generated in the adult kidney
Growth of the contralateral kidney after unilateral nephrectomy
Involves nephron hypertrophy
Replication of proximal tubule cells
In kidney, you take out one kidney, and the other side you will get nephron hypertrophy to increase function and handle the body enough
Process like there were two but in one tissue
Pancreas Regeneration
Limited capacity to regenerate exocrine components and islets
Regeneration of pancreatic beta cells
Beta-cell replication
Transdifferentiation of ductal cells
Differentiation of putative stem cells
Human Liver
Remarkable capacity to regenerate demonstrated by its growth after partial hepatectomy
Tumor resection or for living-donor hepatic transplantation
Resection of approximately 60% of the liver in living donors
Doubling of the liver remnant in about one month
Portions of the liver that remain after partial hepatectomy constitute an intact “mini-liver” rapidly expands and reaches the mass of the original liver
Restoration of liver mass achieved without regrowth of resected lobes
Growth occurs by enlargement of the lobes that remain after the operation= compensatory growth or compensatory hyperplasia
End point of liver regeneration after partial hepatectomy
Restitution of functional mass rather than the reconstitution of the original
Hepatocytes in the Cell Cycle
Hepatocytes are quiescent cells G0 phase, but several hours to enter the cell cycle after a partial hepatectomy
Progress through G1 and reach the S phase of DNA replication
Wave of hepatocyte replication is synchronized followed by synchronous replication of nonparenchymal cells
Kupffer cells, endothelial cells, and stellate cells
Replication of non-paraenchymal cells to make ECM
Restriction Points for Hepatocyte Replication
Two major restriction points for hepatocyte replication:
- G0/G1 transition that bring quiescent hepatocytes into the cell cycle
- G1/S transition needed for passage through the late G1 restriction point
Gene expression in the regenerating liver proceeds in phases
Starts with the immediate early gene response
Transient response that corresponds to the G0/G1 transition
Quiescent Hepatocytes
Become competent to enter the cell cycle through a priming phase mediated by the cytokines TNF and IL-6, and components of the complement system
Priming signals activate several signal transduction pathways as a necessary prelude to cell proliferation
Under the stimulation of HGF, TGFα, and HB-EGF, primed hepatocytes enter the cell cycle and undergo DNA replication
Norepinephrine, serotonin, insulin, thyroid and growth hormone: act as adjuvants for liver regeneration and facilitates the entry of hepatocytes into the cell cycle
Hepatocytes vs. Stem Cell in Compensatory Growth
Individual hepatocytes: replicate once or twice during regeneration and then return to quiescence in a strictly regulated sequence of events
Intrahepatic stem or progenitor cells do not play a role in the compensatory growth that occurs after partial hepatectomy
No evidence for hepatocyte generation from bone marrow-derived cells during this process
ECM and Repair
Tissue Repair and Regeneration depends on:
1 Activity of soluble factors
2. Interactions between cells and the components of the extracellular matrix
Regulates the growth, proliferation, movement, and differentiation of the cells
Functions of ECM: Mechanical, Growth, Maintenance, and Scaffolding
- Mechanical support- cell anchorage and migration, scaffolding, and maintenance of cell polarity (all lined up in a certain way)
- Control of cell growth: ECM components can regulate cell proliferation by signaling through cellular receptors of the integrin family
- Maintenance of cell differentiation: type of ECM proteins affect the degree of differentiation of the cells in the tissue
- Scaffolding for tissue renewal: maintenance of normal tissue structure
Requires a basement membrane or stromal scaffold
Integrity of the basement membrane or the stroma of the parenchymal cells
Critical for the organized regeneration of tissues
Functions of ECM: Microenvironments and Regulatory Molecules
- Establishment of tissue microenvironments: basement membrane boundary between epithelium and underlying connective tissue that forms part of the filtration apparatus in the kidney
- Storage and presentation of regulatory molecules
Growth factors FGF and HGF are secreted and stored in the ECM in some tissues
Allows rapid deployment of growth factors after local injury or during regeneration
Composition of the ECM
Composed of three groups of macromolecules
1. Fibrous structural proteins: collagens and elastins that provide tensile strength and recoil
- Adhesive glycoproteins: connect the matrix elements to one another and to cells
- Proteoglycans and hyaluronan: provide resilience and lubrication (especially to joints)
2 Forms of ECM
- Interstitial matrix: found in spaces between epithelial, endothelial, and smooth muscle cells, as well as in connective tissue
Consists mostly of fibrillar and nonfibrillar collagen, elastin, fibronectin, proteoglycans, and hyaluronan - Basement membranes: closely associated with cell surfaces
Consist of nonfibrillar collagen (mostly type IV), laminin, heparin sulfate, and proteoglycans
Skin
Human epidermis has a high turnover rate: about 4 weeks
Stem cells are located in three different areas of the epidermis
1. Hair follicle bulge: constitutes a niche for stem cells that produce all of the cell lineages of the hair follicle
- Interfollicular areas of the surface epidermis: stem cells are scattered individually in the epidermis and are not contained in niches
Divide infrequently, generate transit amplifying cells, and denerate the differentiated epidermis - Sebaceous glands
Small Intestine Epithelium
Small intestine
1. Crypts: monoclonal structures derived from single stem cells
Stem cells regenerate the crypt in 3 to 5 days
- Villus: differentiated compartment that contains cells from multiple crypts
Skeletal Muscle
Skeletal muscle myocytes do not divide, even after injury
Growth and regeneration of injured skeletal muscle
Occur by replication of satellite cells
Located beneath the myocyte basal lamina
Constitute a reserve pool of stem cells
Generate differentiated myocytes after injury
Cornea
Transparency of the cornea: integrity of the outermost corneal epithelium maintained by limbal stem cells (LSCs)
Located at the junction between the epithelium of the cornea and the conjunctiva
Repair by Connective Tissue
Severe or persistent tissue injury: damage to parenchymal and stromal cells
Leads to a situation in which repair cannot be accomplished by parenchymal regeneration alone
Repair: occurs by replacement of nonregenerated parenchymal cells with connective tissue
4 Steps of Repair by CT
Four components of repair process
- Angiogenesis
- Migration and proliferation of fibroblasts
- Deposition of ECM
- Remodeling (maturation and reorganization of the fibrous tissue)
Tissue Repair
Tissue repair begins within 24 hours of injury
Stimulate the emigration of fibroblasts
Induction of fibroblasts and endothelial
By 3-5 days of tissue repair a specialized type of tissue appears
Characteristic of healing “granulation tissue”
Name from pink soft appearance of tissue seen beneath scab
Characterized by fibroblast proliferation and new, thin walled delicate capillaries
Outcome is formation of dense fibrosis (scarring)
Angiogenesis vs. Vasculogenesis
Blood vessels are assembled by two processes:
Vasculogenesis: assembly of primitive vascular network - from angioblast; in fetus only
Angiogenesis or neovascularization: pre-existing blood vessels send out capillary sprouts
Angiogenesis
Critical process in the healing at sites of injury
Development of collateral circulations at sites of ischemia is stimulated following MI or atherosclerosis
Allows tumors to grow: inhibit blood flow to “starve” tumor growth
Steps of Angiogenesis
- Vasodilation: response to nitric oxide
VEGF-induced increased permeability of the preexisting vessel - Proteolytic degradation of the basement membrane of the parent vessel; use matrix metalloproteinases (MMPs)
Disruption of cell-to-cell contact between endothelial cells by plasminogen activator - Migration of endothelial cells toward the angiogenic stimulus
- Proliferation of endothelial cells just behind the leading front of migrating cells
- Maturation of endothelial cells: includes inhibition of growth and remodeling into capillary tubes
- Recruitment: periendothelial cells, pericytes and vascular smooth muscle cells to form the mature vessel
Angiogenesis: FGF
FGF (fibroblast growth factor)
Mainly FGF-2
Stimulates proliferation of endothelial cells
Promotes migration of macrophages and fibroblasts to the damaged area
Stimulates epithelial cell migration to cover epidermal wounds
Angiogenesis: VEGF
VEGF (vascular endothelial growth factor)
Mainly VEGF-A
Stimulates both migration and proliferation of endothelial cells
Initiating the process of capillary sprouting in angiogenesis
Promotes vasodilation by stimulating the production of NO
Contributes to the formation of the vascular lumen
*helps with sprouting of new vessels
Cutaneous Wound Healing: Steps
Divided into three phases
1. Inflammation: initial injury causes platelet adhesion and aggregation and formation of a clot in the surface of the wound
- Proliferation: formation of granulation tissue, proliferation and migration of connective tissue cells, and re-epithelialization of the wound surface; 3-5 days
- Maturation: involves ECM deposition, tissue remodeling, and wound contraction
* Phases overlap; separation is somewhat arbitrary
Primary Union/First Intention
Simplest type of cutaneous wound repair: healing of a clean, uninfected surgical incision
Approximated by surgical sutures
Referred to as healing by primary union or by first intention
Wound Healing: Incision
Death of a limited number of epithelial and connective tissue cells
Disruption of epithelial basement membrane continuity
Re-epithelialization to close the wound
Occurs with formation of a relatively thin scar
Excisional Wounds
Excisional wounds
Repair process is more complicated
Create large defects on the skin surface
Extensive loss of cells and tissue
Wound Healing with Secondary Union
More intense inflammatory reaction
Formation of abundant granulation tissue
Extensive collagen deposition
Leading to the formation of a substantial scar that generally contracts
Healing by secondary union or by second intention
Pull a wound together, but have granulation tissue deposition and collagen deposition
If you don’t have a suture close the wound: a lot of granulation tissue and collagen = secondary union by second intention
Secondary: big scab, wound contraction and end up with puckering of the skin
Clot Formation: General Information
Wounding causes the rapid activation of coagulation pathways
Formation of a blood clot on the wound surface
Entrapped red cells, fibrin, fibronectin, and complement components
Clot serves to stop bleeding and as a scaffold for migrating cells
Attracted by growth factors, cytokines and chemokines released into the area
Release of VEGF: increased vessel permeability and edema
Clot Formation: Scabs
Dehydration occurs at the external surface of the clot
Forms a scab that covers the wound
Within 24 hours, neutrophils appear at the margins of the incision
Use the scaffold provided by the fibrin clot to infiltrate in
Release proteolytic enzymes that clean out debris and invading bacteria
In a cutaneous lesion, neutrophils appear within 24 hours… 6-24 hours for acute inflammation
Formation of Granulation Tissue
Fibroblasts and vascular endothelial cells
Proliferate in the first 24 to 72 hours of the repair process
Form a specialized type of tissue
Granulation tissue: HALLMARK OF TISSUE REPAIR
Appearance of Granulation Tissue
Granulation tissue: pink, soft, granular appearance on the surface of wounds
Histologic feature: presence of new small blood vessels (angiogenesis) and proliferation of fibroblasts
*Usually see edema because new vessels will be leaky
Granulation Tissue & Edema
New vessels are leaky, which allow the passage of plasma proteins and fluid into the extravascular space
New granulation tissue is often edematous
Progressively invades the incision space
Amount of Granulation Tissue Formed
Amount of granulation tissue that is formed depends on:
Size of the tissue deficit created by the wound
Intensity of inflammation
Much more prominent in healing by secondary union
By 5 to 7 days, granulation tissue fills the wound area and neovascularization is maximal
Neutrophils & Repair
Neutrophils are largely replaced by macrophages by 48 to 96 hours
Macrophages are key cellular constituents of tissue repair
Clearing extracellular debris, fibrin, and other foreign material at the site of repair
Promoting angiogenesis and ECM deposition
Functions of Macrophages
- Debridement/Removal of injured tissue and debris via phagocytosis, collagenase, and elastase
- Antimicrobial activity using nitric acid and ROS
- Chemotaxis and proliferation of fibroblasts and keratinocytes via PDGF, TGF beta, TNF, IL-1, and KGF-7
- Angiogenesis via VEGF, FGF-2, and PDGF
- Deposition and remodeling of ECM: TGF beta, PDGF, TNF, OPN, IL-2, collagenase, and MMPs
Fibroblast Migration
Migration of fibroblasts to the site of injury driven by chemokines TNF, PDGF, TGF-β, and FGF
Proliferation is triggered by multiple growth factors
PDGF, EGF, TGF-β, FGF, and the cytokines IL-1 and TNF
Macrophages are the main source for these factors
Need fibroblasts and go to site of injury via chemokines that attract them
Collagen Fibers and Collagen Deposition
Collagen fibers are present at the margins of the incision, which are vertically oriented and do not bridge the incision
24 to 48 hours, spurs of epithelial cells move from the wound edge along the cut margins of the dermis, depositing basement membrane components as they move.
Fuse in the midline beneath the surface scab producing a thin, continuous epithelial layer that closes the wound (re-epithelializing)
Primary vs. Secondary Intention Re-Epithelialization
Full epithelialization of the wound surface
Much slower in healing by secondary union because the gap to be bridged is much greater
Subsequent epithelial cell proliferation thickens the epidermal layer
In primary intention: quick fix
Secondary intention: takes a lot longer to re-epithelialize
Macrophages & Skin Re-Epithelialization
Macrophages stimulate fibroblasts to produce FGF-7 (keratinocyte growth factor) and IL-6, which enhance keratinocyte migration and proliferation
Signaling through the chemokine receptor CXCR 3 also promotes skin re-epithelialization
Helps to proliferate the surface of the skin and get rid of scab: IL-6 and FGF-7
Start to see underneath dermis that the collagen fibers become more dense
Collagen Replacement of Matrix
Concurrently with epithelialization collagen fibrils become more abundant and begin to bridge the incision
Provisional matrix containing fibrin, plasma fibronectin, and type III collagen is formed
Replaced by a matrix composed primarily of type I collagen
Type III collagen replaced by type I because it is much stronger
TGF-β
TGF-β is the most important fibrogenic agent
Produced by most of the cells in granulation tissue
Causes fibroblast migration and proliferation, increased synthesis of collagen and fibronectin, and decreased degradation of ECM by metalloproteinases
Need more fibroblasts, fibronectin and collagen production to produce the scar
Blanching
Leukocytic infiltrate, edema, and increased vascularity disappears during the second week and blanching begins
Blanching: increased accumulation of collagen within the wound area and regression of vascular channels
Encouraging scar to form and not allowing anything else to break down
During the 2nd week, the swelling, redness, etc is gone without an infection present and the scar is present after the scab falls off
Scar at First Month
Original granulation tissue scaffolding is converted into a pale, avascular scar
By the end of the first month
Scar is made up of acellular connective tissue devoid of inflammatory infiltrate, covered by intact epidermis
Wound Contraction
Generally occurs in large surface wounds
Contraction helps to close the wound by decreasing the gap between its dermal edges and by reducing the wound surface area
Important feature in healing by secondary union
Replacement of granulation tissue with a scar
Involves changes in the composition of the ECM
Recovery of Tensile Strength
Fibrillar collagens (mostly type I collagen)
Form a major portion of the connective tissue in repair sites
Essential for the development of strength in healing wounds
Net collagen accumulation depends not only on increased collagen synthesis but also on decreased degradation
Timeline for Wound to Achieve Maximal Strength
Length of time for a skin wound to achieve its maximal strength
Sutures are removed from an incisional surgical wound
End of the first week, wound strength is approximately 10% that of unwounded skin
Wound strength increases rapidly over the next 4 weeks
Slows down at approximately the third month after the original incision
Reaches a plateau at about 70% to 80% of the tensile strength of unwounded skin
Process of Recovery of Tensile Strength
Lower tensile strength: healed wound area may persist for life
Recovery of tensile strength
Results from the excess of collagen synthesis over collagen degradation during the first 2 months of healing
Structural modifications of collagen fibers (cross-linking, increased fiber size) after collagen synthesis ceases
Wound Repair Impairment
Adequacy of wound repair may be impaired by systemic and local host factors
Systemic factors include:
- Nutrition: protein deficiency: Esp vitamin C deficiency, inhibit collagen synthesis and retard healing
- Metabolic status: diabetes mellitus is associated with delayed healing, a consequence of the microangiopathy
Circulatory Status and Hormones in Wound Healing
Circulatory status:
Modulate wound healing
Inadequate blood supply, usually caused by arteriosclerosis or venous abnormalities (e.g., varicose veins) that retard venous drainage, also impairs healing
Hormones:
Glucocorticoids: well-documented anti-inflammatory effects and influence various components of inflammation
Agents also inhibit collagen synthesis
Factors that Delay Wound Healing
Infection: sesults in persistent tissue injury and inflammation
Mechanical factors:
Early motion of wounds, can delay healing
Compressing blood vessels and separating the edges of the wound
Foreign Bodies and Wound Factors in Healing
Foreign bodies: unnecessary sutures or fragments of steel, glass, or even bone, constitute impediments to healing
Size, location, and type of wound:
Richly vascularized areas, such as the face, heal faster than those in poorly vascularized ones, such as the foot
Small incisional injuries heal faster and with less scar formation than large excisional wounds or wounds caused by blunt trauma
Factors That Retard Wound Healing
Local Factors: blood supply, denervation, local infection, foreign body, hematoma, mechanical stress, necrotic tissue, protection (dressings), surgical techniques, type of tissue
Systemic Factors: age, anemia, drugs, genetic disorders, hormones, diabetes, malignant disease, malnutrition, obesity, systemic infection, temperature, trauma, hypoxia, uremia, vitamin deficiency, trace metal deficiency (zinc and coppe
Complications of Wound Healing
Arise from abnormalities; three categories
- Deficient scar formation
- Excessive formation of the repair components/ scar formation
- Formation of contractures
Deficient Scar Formation
Lead to two types of complications
1. Wound dehiscence: rupture of a wound is most common after abdominal surgery due to increased abdominal pressure caused by vomiting, coughing, or ileus
- Ulceration: inadequate vascularization during healing
Areas devoid of sensation
Excessive Formation of Scar Tissue
Excessive formation of the components of the repair process can give rise to hypertrophic scars and keloids
Accumulation of excessive amounts of collagen may give rise to a raised scar
Hypertrophic scar: develop after thermal or traumatic injury and involves the deep layers of the dermis
Keloid: individual predisposition and more common in African Americans; dense collagen bundles that can arise from a specific dermatome from surgerical incision
Exuberant Granulation
Deviation in wound healing
Formation of excessive amounts of granulation tissue
Protrudes above the level of the surrounding skin
Blocks re-epithelialization
Must be removed by cautery or surgical excision to permit restoration of the continuity of the epithelium
Wound Contraction
Important part of the normal healing process
Exaggeration of this process gives rise to contractures and results in deformities of the wound and the surrounding tissues
Contractures are particularly prone to develop on the palms, the soles, and the anterior aspect of the thorax
Contractures are commonly seen after serious burns and can compromise the movement of joints
Fibrosis
Denote the excessive deposition of collagen and other ECM components in a tissue
Deposition of collagen in chronic diseases
End Result of Chronic Inflammation
Chronic Inflammation (persistent stimulus) causes:
- Activation of macrophages and lymphocytes, which activate growth factors (PDGF, FGF, and TGF beta)
- Cytokines (TNF, IL-1, IL-4, and IL-13)
- Decreased metalloproteinase activity
GF cause proliferation of fibroblasts, endothelial cells, and specialized fibrogenic cells
Cytokines cause increased collagen synthesis
Decreased metalloproteinase activity causes decreased collagen degradation
*END RESULT = FIBROSIS
Injury: Persistent Stimulus vs. Stimulus Removed
Injury and vascular response Persistent tissue damage= fibrosis caused by chronic inflammatory diseases Stimulus removed (acute injury): regeneration and repair
Regeneration (restitution of normal structure) if parenchymal cell death with intact tissue framework, superficial wounds, and acute inflammatory process
Repair (scar formation) if parenchymal cell death with damaged tissue framework or deep wounds
