Understanding Systemic Inflammatory Response and Tissue Repair

1. Healing and tissue repair Assist.Prof.Dr. Baydaa H.Abdullah

3. Systemic inflammatory response • Acute Phase Response • Fever • Acute-phase protein secretion from liver • Leukocytosis • Tachycardia, increased blood pressure • Shivering, chills • Anorexia, somnolence, malaise • Septic shock

4. Acute Phase Proteins • Secretion of Acute Phase proteins by the liver • C-reactive Protein (CRP) • Serum Amyloid A (SAA) • Serum Amyloid P (SAP) • Complement • Fibrinogen • Prothrombin • Ferritin • Ceruloplasmin • α1-antitrypsin • α2-macroglobulin • Acute phase proteins bind: • Microbial constituents, acting as opsonins to fix complement • Chromatin, aiding early clearing of necrotic cells

5. Autonomic and Behavioral Responses • Autonomic • redirection of blood flow from cutaneous to vascular bed • increased pulse and blood pressure • decreased sweating • Behavioral • Rigors (Shivering) • Chills • Anorexia • Somnolence • Malaise

6. Sepsis • Systemic Inflammatory Response Syndrome involves two or more of the following • temperature >38.3ºC or <36ºC • heart rate >90 beats/min; <32 mm Hg • respiratory rate >20 breaths/min, PaCO2 or need for mechanical ventilation • WBC count >12,000/uL or <4,000/uL or >10% immature forms (bands) • Sepsis is defined as SIRS associated with suspected or confirmed infection--positive blood cultures are not necessary • Severe sepsis is sepsis complicated by a predefined organ dysfunction • Septic shock is cardiovascular collapse (hypotension) related to severe sepsis despite adequate fluid resuscitation

7. Septic stimuli • Gram-negative bacteria • LPS, endotoxin • Binds to LPS binding protein (LBP) • Binds to CD14 opsonin receptor • TLR-4 binds LPS and LPS-LBP • Stimulates release of TNF, IL-1, IL-6 • Gram-positive bacteria • Exotoxins, superantigens • Bind Vb regions of TCRs and/or to MHC-II • TLR-2 binds cell wall components • Stimulates release of IFN-g, TNF, IL-1, IL-6

8. Progression of sepsis • Cytokine release and amplification • Vasular response and neutrophil migration • Coagulation cascade • Counter-inflammatory response • Apoptosis of Th and B-cells • Systemic acute phase response • increased cortisol production and release of catecholamines • upregulation of adhesion molecules • release of prostanoids and platelet-activating factor (PAF) • Organ failure

9. Multiple organ failure • Neutrophils damage tissue directly by releasing lysosomal enzymes and superoxide-derived free radicals • TNF-α induces nitric oxide synthase • nitric oxide causes further vascular instability • contributes to direct myocardial depression • Widespread vasodilation • Decreased production of vasopressin (ADH) and glucocorticoids • Circulatory collapse and tissue hypoxia

10. Restoration of Structure and Function • Occurs if connective tissue structure relatively intact • Surviving parenchymal cells must have the capacity to regenerate • Labile Cells • Actively divide throughout life • cells of the epidermis and gastrointestinal mucosa • cells lining surface of the genitourinary tract • hematopoietic cells of the bone marrow • Stable Cells • Undergo few divisions normally, but can be activated from G0 cells when needed • hepatocytes • renal tubular cells • parenchymal cells of glands • mesenchymal cells (smooth muscle, cartilage, connective tissue, endothelium, osteoblasts)

11. Regeneration • Proliferation of cells and tissues to replace lost structures • Whole organs and complex tissues rarely regenerate after injury • Compensatory growth rather than true regeneration • Liver hypoplasia and kidney hypertrophy • Continuously renewing tissues regenerate after injury if tissue stem cells are not destroyed

12. Stem Cells • Characterized by self-renewal properties and capacity to generate differentiated cell lineages • embryonic stem cells (ES cells) are pluripotent • adult (somatic) stem cells are restricted by niche • skin, gut lining, cornea, hematopoietic tissue

13. Stem Cells in Homeostasis and Healing • Bone marrow • Hematopoietic Stem Cells generate all of the blood cell lineages • Marrow Stromal Cells generate precursors of tissue to which migrated • Liver • Oval cells are bipotential progenitors of hepatocytes and biliary cells • Brain • Neural precursor cells generate neurons, astrocytes, and oligodendrocytes • Skin • Hair follicle bulge, interfollicular areas of the surface epidermis, and sebaceous glands • Intestinal epithelium • crypts are monoclonal structures derived from single stem cells • villus contains cells from multiple crypts • Skeletal and cardiac muscle • satellite cells beneath the myocyte basal lamina generate differentiated myocytes after injury • Cornea • limbal stem cells maintain corneal transparency

16. Proliferative capacity of tissues • Labile tissues • Continuously dividing tissues containing stem cells • Stable tissues • Parenchymal cells of solid organs in G0 • Endothelial cells, fibroblasts, smooth muscle • Limited regeneration after wounding • Permanent tissues • Absolutely nonproliferative • Cardiac muscle, neurons

17. Growth factors • Polypeptides that promote survival and proliferation by signal transduction • Increase in cell size • true growth factors • Increase in cell number • mitogens • Protection from apoptosis • survival factors

18. Growth Factor-mediated Proliferation • Platelet Derived Growth Factor (PDGF) • promotes the chemotactic migration of fibroblasts and smooth muscles • chemotactic for monocytes • competence factor that promotes the proliferative response of fibroblasts and smooth muscles upon concurrent stimulation with progression factors • Epidermal Growth Factor (EGF) • promotes growth for fibroblasts, endothelial and epithelial cells • is a progession factor - promotes cell-cycle progression. • Fibroblast Growth Factor (FGF) • promote synthesis of fibronectin and other extracellular matrix proteins • chemotactic for fibroblast and endothelial cells • promotes angiogenesis • links extracellular matrix components (collagen, proteoglycans) and macromulocules (fibrin, heparin) to cell-surface integrins. • Transforming Growth Factors (TGFs) • TGF-α - similar to EGF • TGF-β - mitosis inhibitor that aids in modulating the repair process. May be responsible for hypertrophy by preventing cell division. Chemotactic for macropahges and fibroblasts • Macrophage-derived cytokines (IL-1 and TNF) • promote proliferation of fibroblasts, smooth muscle and endothelial cells

19. Repair Process • Removal of Debris • begins early and initiated by liquefaction and removal of dead cells and other debris • Formation of Granulation Tissues • connective tissue consisting of capillaries and fibroblasts that fills the tissue defect created by removal of debris • Scarring • fibroblasts produce collagen until granulation tissue becomes less vascular and less cellular • progessive contraction of the wound occurs, resulting in deformity of original structure

20. Tissue Repair • Necessary when barriers are penetrated • Cells must divide and migrate • Occurs in two major ways • Regeneration • Same kind of tissue replaces destroyed tissue • Original function restored • Fibrosis • Connective tissue replaces destroyed tissue • Original function lost

21. Slide 1 Figure 4.12. Tissue repair of a nonextensive skin wound: regeneration and fibrosis. Scab Epidermis Vein Blood clot in incised wound Inflammatory chemicals Migrating white blood cell Artery Inflammation sets the stage: • Severed blood vessels bleed. • Inflammatory chemicals are released. • Local blood vessels become more permeable, allowing white blood cells, fluid, clotting proteins, and other plasma proteins to seep into the injured area. • Clotting occurs; surface dries and forms a scab.

22. Regenerating epithelium Area of granulation tissue ingrowth Fibroblast Macrophage Budding capillary 2 Organization restores the blood supply: • The clot is replaced by granulation tissue, which restores the vascular supply. • Fibroblasts produce collagen fibers that bridge the gap. • Macrophages phagocytize dead and dying cells and other debris. • Surface epithelial cells multiply and migrate over the granulation tissue.

23. Steps in Tissue Repair • Regeneration and fibrosis • The scab detaches • Fibrous tissue matures; epithelium thickens and begins to resemble adjacent tissue • Results in a fully regenerated epithelium with underlying scar tissue

24. Slide 3 Figure 4.12. Tissue repair of a nonextensive skin wound: regeneration and fibrosis. Regenerated epithelium Fibrosed area Regeneration and fibrosis effect permanent repair: • The fibrosed area matures and contracts; the epithelium thickens. • A fully regenerated epithelium with an underlying area of scar tissue results. 3

25. Healing and granulation • Fibroplasia is a response to • Damaged connective tissue • Parenchymal damage exceeds regenerative capacity • Hyperplasia of connective tissue • Neovascularization • Granulation • coordinated proliferation of fibroblasts with a rich bed of capillaries • intensely hyperemic with a roughened or granular, glistening surface • healthy granulation tissue resists secondary infections

26. Healing by First Intention • Clean, surgical incision or other clean narrow cut • Focal disruption of epithelial basement membrane with little cell damage • Regeneration dominates fibrosis • Scabbing with fibrin-clotted blood • Neutrophils migrate to edges • Epidermis becomes mitotic and deposits ECM • Macrophages replace neutrophils • Vascularization and collagen deposition fills gap • Contraction of collagen minimizes epidermal regeneration

27. Healing by Second Intention • Larger area of tissue injury such as abcess, ulcer, infarction that destroys ECM • Large clot or scab with fibrin and fibronectin fills gap • Larger volume of necrotic debris must be removed by more neutrophils and macrophages • Opportunity for collateral damage by phagocytes • Scar tissue formed from vascular cells, fibroblasts, and myofibroblasts • Contraction of myofibroblasts distorts tissue • More prone to infection

31. Regenerative Capacity in Different Tissues • Regenerate extremely well • Epithelial tissues, bone, areolar connective tissue, dense irregular connective tissue, blood-forming tissue • Moderate regenerating capacity • Smooth muscle and dense regular connective tissue • Virtually no functional regenerative capacity • Cardiac muscle and nervous tissue of brain and spinal cord • New research shows cell division does occur • Efforts underway to coax them to regenerate better

32. Aging Tissues • Normally function well through youth and middle age if adequate diet, circulation, and infrequent wounds and infections • Epithelia thin with increasing age so more easily breached • Tissue repair less efficient • Bone, muscle and nervous tissues begin to atrophy • DNA mutations possible  increased cancer risk

33. Factors that Impede Repair • Retention of debris or foreign body • Impaired circulation • Persistent infection • Metabolic disorders • diabetes • Dietary deficiency • ascorbic acid • protein

34. Keloid—excessive cutaneous fibrosis