Inflammation and Tissue Repair

• Study notes on tissue healing

Key Concepts

• Pathology is defined as structural or functional changes in the body caused by disease or trauma.
• Cell injury leads to inflammation, which then leads to tissue healing.

Physical Stress Theory

• The Physical Stress Theory describes how tissues adapt to stress.
• Adaptations include atrophy, maintenance, hypertrophy, injury, and death.
• Exposure to stress is a composite of the magnitude of force, time, and direction of the force.
• Other factors affecting response to stress include age, PMH, medications, activity level, obesity, nutrition, and body mechanics.
• Injury can be caused by high-magnitude stress over a short duration, low-magnitude stress over a long duration, or moderate-magnitude stress applied frequently.

Cell Injury Details

• Cell injury can occur due to infection, ischemia, immune response, genetic factors, nutritional factors, chemical factors, or physical factors like trauma or temperature.
• The type of injury depends on the mechanism, severity, and timeline of intervention.
• There are two types of cell injury: reversible and irreversible.

Reversible Cell Injury

• Reversible cell injury is a sublethal, transient alteration.
• Removal of the stressor leads to a return of normal structure or function.
• Cells can adapt to chronic sublethal injury.
• Acute reversible cell injury involves increased intracellular sodium and calcium, and intracellular swelling.
• Intracellular swelling specifically affects the cytosol, mitochondria, and endoplasmic reticulum.
• The pH of the cell lowers.
• Removal of the stressor reverses the process.
• Chronic sublethal cell injury involves stress maintained, leading to possible adaptations like atrophy, hypertrophy, hyperplasia, metaplasia, or dysplasia.

Irreversible Cell Injury

• Irreversible cell injury leads to cell death.
• Hallmarks of cell death include alterations in the nucleus, changes in the mitochondria and lysosomes, rupture of the cell membrane, and necrosis.
• Byproducts are released into the circulation and can be measured with blood tests.

Body’s Response to Cell Injury: Inflammation

• Inflammation can result from trauma, bacteria, or toxins.
• Inflammation breaks down and removes dead cells and debris.
• Inflammation initiates tissue healing.
• Response depends on the amount, type, and severity of injury.
• Innate immune responses like neutrophils and macrophages are initiated, as are pro-inflammatory mediators like cytokines, interleukins (IL), tumor necrosis factor (TNF), and growth factors (GF).

Acute Versus Chronic Inflammation

• Acute inflammation has a fast onset and short duration.
• Hallmarks of acute inflammation are edema from exudate, erythema, warmth to the touch, and pain.
• Chronic inflammation has a prolonged duration.
• Hallmarks of chronic inflammation are accumulation of macrophages and lymphocytes, hypervascularity and fibrosis, and tissue necrosis.
• Chronic can occur with unaddressed injuries, burns, or wounds with wide edges, or when regeneration isn't possible.
• Chronic inflammation can also arise from repeated episodes of acute inflammation, patient noncompliance, or uncorrected faulty movement mechanics.

Chemical Mediators of Inflammation

• Histamine is stored in mast cells, basophils, and platelets.
• Histamine increases vascular permeability and acts as a vasodilator and bronchoconstrictor.
• Platelet Activating Factor is derived from phospholipids, causes platelet aggregation and secretion, and increases leukocyte concentration.
• Arachidonic Acid Derivatives: There are two pathways; Cyclooxygenase pathway (Prostaglandins) and Lipoxygenase pathway (Leukotrienes).
• Prostaglandins increase platelet aggregation and mediate fever and pain.
• Leukotrienes increase vascular permeability, chemotaxis of leukocytes, and bronchoconstriction.
• Medications like corticosteroids and NSAIDs can block inflammatory responses.
• Interleukin-1 (IL-1) and Tumor Necrosis Factor (TNF) are produced by leukocytes.
• Cytokines produce local and systemic effects, induce fever, increase metabolism, and cause hemodynamic changes.

Components of Tissue Healing

• Collagen is the most important structural support, and provides tensile strength for all tissues.
• Organization determines structural properties.
• In tendons, collagen fibers are organized in parallel bundles, while in skin and bone, they are randomly oriented.
• Type I collagen is most common, thick-bundled, and very strong.
• Type II collagen is thin and found specifically in the growth plate.
• Type III collagen is thin, supple, and elastic.
• During repair, Type III collagen is secreted in large amounts, then is degraded and replaced by Type I during maturation.
• Fibronectin forms a scaffold for repair and acts as a "glue".
• Fibronectin is an early stabilizer of healing tissue, helps fibrin form a clot, and draws fibroblasts and macrophages.
• Proteoglycans and elastin are secreted by fibroblasts, bind to fibronectin and collagen, and hydrate tissue.

Tissue Healing Influences

• Factors that affect tissue healing include age, co-morbidities, medications, infection, activity level, local blood supply, nutrition, smoking, stress, and exercise.
• Causes of tissue damage include repetitive pathologic movement (overuse), trauma, and/or surgery.

Stages of Tissue Healing

• The stages include hemostasis & degeneration, inflammation, proliferation & migration, and maturation/remodeling.

Hemostasis & Degeneration

• This stage occurs immediately post-injury and lasts up to 24 hours.
• Its purpose is to limit blood loss.
• Damage occurs to endothelial cells of vessels.
• This activates the cascade of coagulation pathways.
• Platelets adhere to the subendothelial layer of vessels, forming a clot and releasing growth factors, which summon inflammatory cells.
• Blood coagulation involves intrinsic and extrinsic pathways leading to a common pathway involving Hageman Factor XII.
• The system results in Prothrombin converting to Thrombin, leading to Fibrinogen converting to Fibrin (clot).
• The fibrinolytic system lyses blood clots and involves plasmin.
• The Kinin Enzymatic System produces Bradykinin which causes vasodilation and induces pain.
• The Complement System involves vasodilation, chemotaxis of leukocytes, and activation of Anaphylatoxin.

Inflammation Phase

• Lasts up to 5 days post injury.
• Clears the wound site of foreign bodies and harmful substances through leukocytes and plasma proteins.
• Summons cells that will form new tissue, like fibroblasts, epithelial cells, and vascular endothelial cells.
• Local vasodilation and increased capillary permeability occurs.
• Exudation involving plasma proteins and WBCs move from intravascular space to injury site.
• Leukocytes attach and go into the vascular space into interstitial space

Leukocytes

• Margination: WBC attach to endothelial cells of blood vessels
• Diapedesis: WBC move from intravascular space to interstitial space
• Chemotaxis: WBC follow the injury
• Diagnostic of inflammation
• Neutrophils are the initial immune cells that phagocytize debris and digest bacteria, releasing enzymes that break down ECM of damaged tissue.
• Neutrophils undergo apoptosis and are ingested by Macrophages.
• Monocytes and macrophages arrive 72 hours after injury and are primary immune cells.
• They stimulate the release of anti-inflammatory mediators and shifts phenotypic expression of macrophages from M1 (pro-inflammatory) to M2 (anti-inflammatory).
• Promotes Angiogenesis, Scar Formation, and Matrix Production.

Proliferation & Migration Stage

• The Phase lasts from days 4-21 and is a Tissue Repair Phase.
• Fibrin clot is replaced with disorganized ECM.
• Fibroblasts are attracted to the area and are stimulated by growth factors like Platelet-Derived Growth Factor (PDGF), Transforming Growth Factor Beta (TGF-B), Fibroblast Growth Factor (FGF), and Insulin-like Growth Factor-1.
• Type III collagen is synthesized.
• Fibrin forms a temporary scaffold for tissue repair (Fibroplasia).
• Platelets are important for angiogenesis involved in the release of PDGF and Vascular Endothelial Growth Factor (VEGF).
• Granulation tissue consists of fibroblasts and new blood vessels within disorganized ECM.
• Fibroblasts convert to myofibroblasts, which exhibits contractile characteristics.
• End result is scar formation.

Maturation & Remodelling

• Lasts from day 21 up to 1-2 years.
• Scars mature.
• Type I collagen is the major extracellular component.
• There is mechanical strength as scar tissue increases.
• Increased collagen diameter and cross-linking occurs.
• Tissue can undergo repair which includes restoration of structural integrity.
• Tissue properties are impaired versus pre-injury levels and tissue is never as good as the original tissue.
• Regenerated tissue restores preinjury state as a result of new cells.

Rehabilitation Considerations

• Inflammatory considerations are control edema, minimize pain, PROM of involved tissue, grade I/II mobilizations, AROM of surrounding tissues and introduce sub-max isometrics.
• Avoid anti-inflammatories and stretch.
• Proliferation & Subacute include tissue to influence collagen alignment, prevent scar contracture, AROM of involved tissue, Grade III/IV mobilizations, stretching, submax isometrics, introduce resistance, and neuromuscular re-education.
• For Maturation/Chronic include return to function, regain full pain-free motion, perform grade IIII/IV mobilizations, stretching progress, perform resistance training, sport exercises, agility, and plyos.

Tissue Repair Details

• Injury to skeletal muscle can result from intrinsic forces (strain) or extrinsic forces (contusion, laceration).
• Skeletal muscle has excellent healing potential.
• Re-injury and fibrosis can hamper repair.
• Fibrosis is excess ECM material at the site of repair.
• Continued myofibroblast activity causes prolonged inflammation which causes release of cytokines.
• Disorganized collagen continually is deposited and limits biomechanic movement.
• High Soft Tissue Injury Classifications grade 1 is low damage and grade III is high structural damage.
• Muscle is likely to retract if fully damaged.
• It has potential for regeneration due to satellite cells.
• Repair includes scar being initially weak- chance of reinjury and strengthens in 2 weeks.
• Myofibers connect to scar.s
• Guided motion is necessary to optimize healing and tissue alignment.

Rhabdomyolysis

• Rhabdomyolysis is a severe, rapid breakdown of muscle cells with the release of contents into circulation.
• This can lead to renal failure.
• Risk factors for rhabdomyolysis include ephedra, high doses of statins, and high levels of strenuous exercise.

Tendons/Ligaments

• Consists of connective tissue and Type I collagen.
• MOIs are rapid in unique directions or can occur due to degenerative chances.
• It has low vascularity and slow healing that leads to adhesions to other bones. There is a high risk of injury.
• Tendon ruptures include macroscopic failure from forces exceeding physiological capacity and often rapid force in oblique direction.
• Lacerations happen at wrist.
• Tendinopathy results from overuse and repair varies by location
• Hemostasis occurs in the first -72 hours
• Inflammatory/Proliferative occurs from 2-3 weeks.
• Maturation occurs for 3 weeks by replacing III to I collagen.

Chronic Tendinopathy Details

• Chronic Tendinopathy is disordered healing of tissue and macrophages.
• It includes Collagen degeneration and necrosis irregular collagen and new tissue and added ground tissue.
• Sprains and tears near contribute to instability where they heal like tendons, with remodeling (slow degradation) and decreased stability

Cartilage

• Consists of chondrocytes, proteoglycans, and collagen
• Types exist as articular (hyaline), fibrocartilage, elastic and fibroelastic
• Has poor healing, it is avascular without synovtail fluid

Test your knowledge of inflammation, tissue repair, and chemical mediators. Questions cover regeneration failure, vascular permeability, bronchoconstriction, collagen organization after tendon injury, and effects of cyclooxygenase pathway blockers. Also includes Physical Stress Theory.