1. Inflammation and Repair Windsor University SOM Dr Bikramajit Singh Saroya

2. Chronic Inflammation Chronic inflammation is a response of prolonged duration (weeks or months) In which inflammation, tissue injury and attempts at repair coexist, in varying combinations. Chronic inflammation Unlike acute inflammation has: Mononuclear cell infiltrate Induration of affected tissue. Less swelling (less exudate) Less hyperemia (redness)

3. ACUTE INFLAMMATIONCHRONIC INFLAMMATION PathogenesisMicrobial pathogens, trauma, burns Persistent AI, foreign bodies ( silicone, glass), autoimmune disease, certain types of infection (TB, leprosy) Primary cells involvedNeutrophils Monocytes/macrophages (key cells), B and T lymphocytes, plasma cells, fibroblasts Primary mediators Histamine (key mediator), prostaglandins, leukotrienes Cytokines (e.g., IL-1), growth factors NecrosisPresentLess prominent Scar tissueAbsentPresent OnsetImmediateDelayed DurationFew daysWeeks, months, years Outcome Complete resolution, progression to chronic inflammation, abscess formation Scar tissue formation, disability, amyloidosis Main immunoglobulinIgMIgG Mild hypoalbuminemia Polyclonal gammopathy; greater degree of hypoalbuminemia Peripheral blood leukocyte responseNeutrophilic leukocytosisMonocytosis

4. CHRONIC INFLAMMATION- Etiology 1.Following acute inflammation. 2. Persistent infections a.Viral infections b.M. tuberculosis (tuberculosis) c.Treponema pallidum (syphilis) d.Fungal infections (histoplasma) e.Parasitic infection 3. Prolonged exposure to toxic agents. a.Silica (silicosis) b.Lipids (atherosclerosis) c.Silicone in breast implants 4. Autoimmune diseases a.Rheumatoid arthritis b.Multiple sclerosis.

5. MORPHOLOGY Chronic inflammation is characterized by Infiltration with mononuclear cells (which include macrophages, lymphocytes, and plasma cells) Tissue destruction (induced by the persistent offending agent or by the inflammatory cells) Attempts at healing by connective tissue replacement of damaged tissue (angiogenesis, fibrosis)

6. MONONUCLEAR PHAGOCYTE SYSTEM Consists of : Circulating blood monocytes and Tissue macrophages (2 types): 1.Fixed macrophages Kupffer cells (liver) Sinus Histiocytes (spleen) Bone (osteoclast) 2. Wandering macrophages Microglia (CNS) Alveolar Macrophages (lung) Remember that tissue macrophages are derived from blood monocytes.

8. Pathways of macrophage activation Classically activated macrophages are induced by microbial products and cytokines (IFN-γ). Macrophages produce Nitric oxide and Reactive oxygen species Upregulate lysosomal enzymes, and enhance ability to kill ingested organisms Alternatively activated macrophages are induced by IL-4 and IL-13, produced by TH 2 cells (a helper T cell subset) and other leukocytes. Secrete growth factors that promote angiogenesis, activate fibroblasts and Stimulate collagen synthesis  Initiate the process of repair

10. LYMPHOCYTES : IN CHRONIC INFLAMMATION Microbes and other environmental antigens activate T and B lymphocytes. Two types of lymphocytes: 1.T cells CD 4 (Helper T cells) CD 8 (Cytotoxic T cells) 2.B Cells

11. T-Cells Interact with macrophages in chronic inflammation Activated by ag presented by macrophages Activated lymphocytes produce IFN gamma IFN gamma activates macrophages Activated macrophages produce IL-1 and TNF that activates lymphocytes and other cells.

12. PATTERNS OF CHRONIC INFLAMMATION 1. Chronic nonspecific inflammation 2. Granulomatous inflammation Chronic nonspecific inflammation: Characterized by – Infiltration by mononuclear cells e.g lymphocytes, macrophages and plasma cells). – Inflammatory response not specific for any particular etiological agent.

13. GRANULOMATOUS INFLAMMATION Definition: specialized form of chronic inflammation characterized by formation of granulomas. Granulomas: are characterized by collections of activated macrophages, often with T lymphocytes, and sometimes associated with central necrosis. Two types: 1.Caseating granulomas and 2.Non-caseating granulomas

14. COMPOSITION OF GRANULOMAS Epithelioid cells – IFN gamma transforms macrophages  epithelioid cells ( hallmark cell of granuloma*) Multinucleated giant cells – Formed by fusion of epithelioid cells – Langhans type giant cells (TB) – Foreign body type of giant cells – May be present ; but not necessary* Lymphocytes, Plasma cells Central caseous necrosis – Seen in granulomas due to tuberculosis, fungal infections. – Rare in other granulomatous diseases.

16. LYMPHATICS AND LYMPHNODES IN INFLAMMATION Filter the Extravascular fluid Represent a secondary line of defense. Lymphatics: – Help to drain edema fluid during inflammation – Can get inflamed : lymphangitis Lymphnodes: – May get inflamed = lymphadenitis. – May get enlarged = lymphadenopathy – If fail to filter the microbes  circulation  bacteremia.

17. TISSUE REPAIR Repair (healing): Restoration of tissue architecture and function after an injury. Repair occurs by two types of reactions:  Regeneration by proliferation of residual (uninjured) cells and maturation of tissue stem cells  Deposition of connective tissue to form a scar Mild epithelial injury: resolution occurs by regeneration Severe injury (with connective tissue damage ): repair is by scar formation

19. Regeneration Replacement of damaged components and return to a normal state Occurs with proliferation of  Cells that survive the injury and retain the capacity to proliferate eg. epithelia of skin and intestines, liver  Tissue stem cells - restoration of damaged tissues. According to the proliferative capacity of their cells. Tissues are classified as labile, stable, and permanent.

20. REPAIR BY CONNECTIVE TISSUE Replacement of damaged tissue by a connective tissue (fibrous tissue) scar. Occurs if : – Tissue architecture is destroyed – Basement membrane is not intact (e.g. third degree burn) 1.Neutrophil transmigration 2.Macrophage transmigration 3.Formation of granulation tissue. 4.Initial production of type III collagen 5.Remodeling of scar tissue

21. Steps in Repair by Connective Tissue 1.Neutrophil transmigration – To liquefy injured tissue and then 2.Macrophage transmigration to – remove the debris. 3.Formation of granulation tissue. A specialized type of newly formed connective tissue. Pink, soft and has granular appearance. Is Highly vascular, Composed of newly formed blood vessels (angiogenesis) and fibroblasts. – Fibroblasts produce collagen Accumulates and eventually produces dense fibrotic scar.

22. Steps in Repair by Connective Tissue 4. Initial production of type III collagen: Collagen: – Major component of fibrous tissue – Produced by fibroblasts – Is a triple helix of cross linked alpha chains. Cross linking increases the tensile strength of collagen. Lysyl oxidase cross links points of hydroxylation (vitamin C mediated) on adjacent alpha chains. Type I collagen in skin, bone and tendon has greater tensile strength than type III collagen in the early phase of tissue repair.

23. Steps in Repair by Connective Tissue 5. Dense scar tissue produced from granulation tissue must be remodeled. – Remodeling increases the tensile strength of scar tissue. – Metalloproteinases (collagenases) replace type III collagen with type I collagen, increasing tensile strength to approx. 80% of the original.

24. Important Growth Factors of Healing Platelet derived growth factor: (PDGF) – Promotes migration and proliferation of fibroblasts and smooth muscle cells – Is chemotactic for monocytes Epidermal growth factor (EGF) – Promotes granulation tissue formation. Vascular endothelial cell growth factor (VEGF) – Stimulates angiogenesis Basic fibroblast growth factor – Stimulates angiogenesis

25. Skin Wounds Healing 1. First intention (primary union) Occurs in clean, uninfected wounds with apposed edges  Ex. surgical incisions approximated by sutures 2. Second intention (secondary union) Occurs in wounds that remain open and are larger and infected  Ex. infarcts, ulcers, abscesses

26. First Intention(Primary Union) Immediately – incision fills with clotted blood (hematoma) – scab covers wound Ist day (Within 24 hrs) – neutrophils begin to accumulate at margin – proliferation of epidermal cells at margin 2 nd day – epithelial cells migrate from basal layer of apposing skin seal off the wound after 48 hours. macrophages emigrate into wound. 3 rd day: Beginning of granulation tissue formation. – Angiogenesis due to basic fibroblast growth factor (BFGF). – Fibroblast lay down type III collagen.

27. First Intention(Primary Union) Fibronectin is the key chemical mediator: – Derived from macrophages / fibroblasts / endothelial cells. – Chemotactic to fibroblast  collagen – Chemotactic to endothelial cells  angiogenesis. – Opsonizing and adhesion agent 4 th – 6 th day – Granulation tissue formation peaks. – Collagen bridges the incision site. Week 2: – Collagen compresses the blood vessels in fibrous tissue, resulting in reduced blood flow. – Tensile strength about 10% of normal.

28. Weeks to months: – Collagenase remodeling of the wound occurs. – Type III collagen replaced by type I collagen to increase tensile strength. – Tensile strength increases reaching 80% within 3 months. – Scar tissue is devoid of adenexal structures (hair, sweat glands) and inflammatory cells.

29. Second Intention(Secondary union) 1.inflammatory reaction is more intense 2.larger amounts of granulation tissue formation 3.larger scar 4.wound contraction – Myofibroblasts: fibroblasts with feature of SMC – Decrease the size of defect significantly as wound heals.

31. Wound Strength Skin wounds – 1 week old; 10% of unwounded skin rapid increase in tensile strength as scar tissue accumulates over 2 months – Completely healed; 70-80% of unwounded skin – Scar tissue is never as strong as the original tissue !!

32. Factors Impairing Wound Healing Infection – MC cause of delayed wounds healing – Persistent injury and inflammation – Staphylococcus MC pathogen Foreign material Size, location & type of wound – wounds in ↑ vascularized areas (face) heal faster than in poorly vasc. areas (tendon, feet) – small wounds heal faster than larger – incisions faster than blunt trauma (contusions)

33. Factors Impairing Wound Healing Nutrition--Leads to structurally weak collagen – Protein deficiency, – Vitamin C deficiency – Zn deficiency – Copper deficiency Metabolic status-- Susceptibility to infection – diabetes mellitus Circulatory status – inadequate blood supply due to atherosclerosis, or vascular defects impairs healing Glucocorticoids: – inhibit collagen synthesis and decrease tensile strength.

34. Complications of Wound Healing 1.Deficient scar formation -- Can lead to Wound Dehiscence (rupture of wound)  most common after abdominal surgery -coughing, vomiting, 2.Excessive formation of repair components  Keloid  Exuberant granulation or proud flesh 3.Exaggerated contraction

35. Keloid Raised scar (tumor like mass) caused due to excessive synthesis of type III collagen. Genetic predisposition. – more common in African Americans Tends to affect the earlobes, face, neck, sternum etc. Micro: – composed of irregular thick collagen bundles extending beyond the original injury

36. Exuberant Granulation(Proud Flesh) and Contracture Excessive granulation tissue Protrudes above surrounding skin Prevents re- epithelization Exaggerated contraction – Due to excessive scar tissue – Can compromise the movement of joints. Most commonly seen in: – palms, soles, anterior thorax following severe burns