YR1 Lecture 1H - Inflammation & Healing 2022 PDF

Inflammation and healing 1 Dr Tristan Rutland B.Pharm MBBS FRCPA @TristanRutland7 Anatomical Pathologist Liverpool Hospital Lecturer in Pathology WSU Medical School One of the five major causes of disease: Hereditary/genetic Trauma Inflammation Neoplasia Degenerative 2 Inflammation is a good thing (...

Inflammation and healing 1 Dr Tristan Rutland B.Pharm MBBS FRCPA @TristanRutland7 Anatomical Pathologist Liverpool Hospital Lecturer in Pathology WSU Medical School One of the five major causes of disease: Hereditary/genetic Trauma Inflammation Neoplasia Degenerative 2 Inflammation is a good thing (normally)! Vital part of immune process Protects against and removes injurious agents (including necrotic cells) Starts healing process Can be triggered inappropriately e.g. hypersensitivity reactions which can cause collateral tissue damage. 3 Inflammation Can cause injury by: Acute death of cells Prolonged/recurrent chronic inflammation Can result in incomplete repair/healing E.g. cirrhosis 4 Inflammation Players Immune cells from the circulation resident in affected tissues Blood vessels of the affected tissues/organs Allow more cells to arrive Chemical mediators Cytokines, Hormones, etc 5 Inflammation Mediators Released from cells both resident or arriving Can be either “pro-inflammatory” and “anti-inflammatory” and interact by being synergistic or antagonistic, Made up of comprise diversity of molecular species complex proteins Peptides organic acids small molecules e.g. NO and oxygen radicals. 6 Inflammation and infection are different Inflammation is: Responses in tissue to injury. Can be caused by other things other microorganisms. Infection is: the presence of micro-organisms in or on tissue. it can occur without inflammation (e.g. colonisation). 7 Inflammation and Healing General Inflammation can be: 1. Acute inflammation : Comes on over hours or a few days. Does not last long - days. Involves small blood vessels and blood leucocytes. 2. Chronic inflammation which: Goes on for weeks, months or years. Involves formation of new blood vessels and fibrous tissue. Healing: The processes by which tissues recover from injury to restore structure and function completely or incompletely. 8 Naked eye appearance of acute inflammation Four principal changes described 2000 years ago as: 1. 2. 3. 4. Redness (rubor) Swelling (tumor) Heat (calor) Pain (dolor) and the fifth added 150 years ago – Due to changes in blood vessels Due to inflammation as result of injury 5. Loss of function (functio laesa) 9 Acute inflammation – acute gout 10 Acute Inflammation - the “stimulus” Infections “pathogenic” micro-organisms: Toxins (“poisons”) splinters, dirt, sutures with physical, chemical and infectious components Dead or injured tissue heat, cold, ionising radiation and mechanical injury, “Foreign bodies” exogenous chemicals agents produced by organisms e.g. anthrax Physical agents bacteria, viruses, fungi and parasites. e.g. dead heart muscle after coronary artery occlusion. Immunological reactions which are harmful, “hypersensitivity” and of four principal types. 11 Acute Inflammation Sequence of principal events 1. Dilation of arteries and capillaries. 2. Increased blood flow. 3. Increased vascular permeability especially post-capillary venules. 4. Oedema, usually protein-rich exudate. 5. Margination of neutrophils then their 6. Emigration into tissue. 12 Vascular events 13 Increased vascular permeability from: Contraction of endothelium producing intercellular gaps; Mediators → e.g. histamine, bradykinin, leukotrienes, substance P. Direct vessel injury Severe burns or lytic infection. Mediators from inflammatory cells ( E.g. neutrophils →oxygen species and proteolytic enzymes) 14 Fibrinous exudate Acute appendicitis Pneumonia 15 Inflammation - Cells Leucocytes – usually neutrophils: NOTE: In viral and autoimmune inflammations lymphocytes (e.g. T cells) may be the main cell type. Erythrocytes: Passive loss through damaged capillaries – “diapedesis”. 16 Margination of neutrophils 17 Lung – Lobar pneumonia Intra alveolar purulent exudate Margination of neutrophils Emigration of neutrophils 18 Acute virus hepatitis – infiltration of lymphocytes 19 Sub-types of Acute Inflammation Principal varieties are: Serous: Fibrinous: Due to large vascular leaks are large or there is a local procoagulant stimulus Fibrinogen (from leak) → causes fibrin → latter organises to fibrous Body cavities e.g. meninges and serosal surfaces Suppurative: Exudation of cell-poor fluid Some protein, small number inflammatory cells Usually occurs → peritoneum, pleura, or pericardium NB: These effusion can also be caused by non-inflammatory conditions living and dead neutrophils are abundant but mixed with products of tissue digestion to form “pus”, an abscess - a localised collection of pus (creates own space vs empyema in potential space) Ulcerative: local defect, or excavation, of the surface of an organ or tissue. Produced by the sloughing (shedding) of inflamed necrotic tissue 20 Fibrinous pericarditis 21 Bronchopneumonia 22 Suppurative meningitis 23 Suppurative inflammation 24 Peptic ulcer Ulcerative inflammation 25 Molecular basis of acute inflammation Involves many chemically diverse mediators. Some pre-formed inside tissue cells and are released soon after injury e.g. histamine from mast cells. Most are synthesised after injury. Actions also include Different mediators can have similar effects local pain and/or systemic effects e.g. fever. (often at different times in the inflammatory process). An individual mediator can produce several different effects. 26 27 28 Inflammation – mediation of vascular events Acting on vascular smooth muscle, include: Histamine Prostaglandins Leukotrienes Nitric oxide. 29 30 31 Inflammation – mediation of cellular events Acting on vascular endothelium and blood leucocytes, - include: Adhesion molecules, selectins and integrins Chemotactic agents cytokines particularly chemokines. 32 33 Outcomes of acute inflammation Complete resolution Partial resolution (healing with fibrous): Chronic inflammation Death 34 Outcome of Acute Inflammation - 1 Complete resolution: Stimulus is neutralised and eliminated, Vascular and cellular reactions reverse and subside, Dead and damaged tissue is removed, Normal structure and function returns fully. 35 Outcome of Acute Inflammation - 2 Death - of the tissue or the whole person: Injuring agent (e.g. virulent micro-organism) cannot be overcome, Inflammation becomes progressively more severe, Tissue dies locally and then putrefies – gangrene or Vital organs are overwhelmed by exogenous toxins and/or products of inflammation, Death due to shock and/or loss of function. 36 Lung abscess 37 Outcome of Acute Inflammation- 3 Partial resolution (healing with fibrous): Death of an area of tissue, Blood vessels and fibroblasts grow in - “organisation”, this mix of capillary vessels and fibroblasts is “granulation tissue”, This matures and becomes less vascular and cellular, Extra-cellular collagen deposited, turns into a scar (fibrosis). 38 Outcome of Acute Inflammation - 4 Chronic inflammation: Some acute inflammation persists but also formation of granulation tissue and fibrosis, may be repeated episodes of acute inflammation and healing e.g. in peptic ulcers. 39 Chronic Inflammation - definition Chronic inflammation: Lasts for weeks to years. Concurrently there is varying: continuing inflammation, tissue injury and healing, often by fibrosis 40 Chronic inflammation - morphology Principal features are: Cellular infiltrate which includes: Macrophages Lymphocytes Plasma cells (but also neutrophils, eosinophils and basophils in variable numbers) Repair with new vessel formation Varying degrees of fibrosis 41 Tissue changes in chronic inflammation - 1 Cellular reaction Predominantly “mononuclear” macrophages from monocytes in the blood – (bone marrow) or from precursor cells resident in the tissue Ingest and destroy microorganisms and dead tissue and secrete chemically active agents. If prolonged can produce tissue injury. 42 Tissue changes in chronic inflammation -2 but also: Neutrophils, particularly in acute flare ups. Other cells of the immune system: lymphocytes plasma cells eosinophils (in hypersensitivity reactions) mast cells (in hypersensitivity reactions) 43 Tissue changes in chronic inflammation In varying proportions: Continuing tissue destruction: ulceration or necrosis may be necrosis of special type e.g. caseous (“cheese-like”) necrosis in tuberculosis and Repair/healing: possible re-growth of specialised cells and with proliferation of small blood vessels (angiogenesis) and fibroblasts to form granulation tissue and more mature scar tissue. 44 Chronic inflammation Effects of fibrosis Scarring with deformity - consequences are: On the body surface, healed ulcers shrink and produce deformity; extreme example “contractures” after severe burns. In hollow organs causes obstruction e.g. pyloric stenosis secondary to peptic ulcer, intestinal strictures in Crohn’s disease. 45 Sub types of chronic inflammation “Non-specific” - as already described. Granulomatous comprising: Standard chronic inflammation and epithelioid histocytes (transformed macrophages) form “granulomas” and +/- formation of syncytial multinucleated giant cells (various: Langhans, foreign-body). 46 “Granuloma” formation 47 Miliary tuberculosis 49 Causes of chronic inflammation? Sequel of acute inflammation AND/OR Start as chronic due to: Persistent infections low acute virulence e.g. Mycobacterium tuberculosis (MAC) Mostly due to a delayed hypersensitivity reaction. Persistent exogenous toxins e.g. silica, asbestos fibres or dead and damaged tissue Auto-immune diseases – self-destructive inflammation 50 Chronic inflammation – mediation Macrophages are the ‘HQ cells’ (drivers) in chronic inflammation. They secrete cytokines ands growth factors, e.g. Recruit other inflammatory cells (usually T cells) Fibroblasts → fibrosis, etc. Direct involvement in destroying foreign invaders 51 Outcomes of chronic inflammation Becomes inactive → Fibrosis Scar tissue (loss of function) Long term disabiltiy Recurrence → e.g. reactivation of TB Persists and becomes fatal TB Amyloidosis Neoplasia 53 Cell and tissue repair/healing Requires cell proliferation by: Remains of injured tissue – (adult) stem cells attempt to restore normal structure. Vascular endothelial cells to produce new vessels. Fibroblasts to produce scar to fill defects not corrected by regeneration. 54 Cell and tissue repair/healing Process is controlled by polypeptide growth factors. Ability of cells to divide in response to these determines adequacy of the repair process. 55 Tissue Repair (healing) Two mechanisms: Regeneration Returns tissue to normal state Proliferation of differentiated cells (from stem cells) Needs framework Connective tissue deposition (scar formation) Tissue too damaged or can not regenerate 56 Examples Regeneration Scar formation 57 58 Regeneration and Healing Regeneration describes a tissue response with: Growth of specialised cells/tissues (i.e. normal structures) is restored instead of being replaced by a scar. For this the normal tissue “framework” must be preserved. Healing - the tissue response to: a wound, often in the skin, inflammation in internal organs, cell necrosis in organs incapable of regeneration. 59 Healing by Regeneration Happens if: Specialized cells of an internal organ (e.g. kidney and liver) are destroyed but, the framework of the organ is preserved. Surviving somatic stem cells proliferate and cover the reticulin fibre framework. Eventually the normal structure is restored. 60 Liver stem cells 61 Healing of wounds This mechanism is similar in skin and internal organs however there are exceptions: fractures of bone, wounds to the brain. 62 Example: healing of a wound in skin This occurs in three phases: Inflammation – early and late, Formation of granulation tissue and re-growth of epithelium, Wound contraction: deposition of extracellular material including collagen, remodelling of the scar. 63 First Intention vs Secondary Intention First Intention is more desirable Minimal scar formation Small, clean, uninfected wounds with severed edges close together (e.g. sutured) 64 A word on tensile strength (in wound healing). Starts low. Increases slowly for ~ 2 weeks then rapidly increases. ~ 6 weeks ~ 50% of its ultimate strength; strong enough to tolerate moderate forces. NB, in a rat model, wounds never achieve more than 80% of pre-wound tensile strength. 70 Secondary Intention Undesirable Usually due to Infection Large defect Ongoing inflammation No opposition of edge of wound Combination of above factors 71 Wound healing by second intention 72 Healing of an ulcerated wound 73 Bone fractures Different process Haematoma Influx of inflammatory cells Inflammatory mediators soft tissue callus → bony callus Woven bone → lamellar bone 76 77 Fracture healing - early Fracture healing - intermediate Fracture healing – late callus 78 Healing of a fracture of the fibula Callus Recent Six weeks later 79 Bone fractures Complications Infection Diseased bone (osteoporosis, metastasis) Inadequate immobilization Above can result in Delayed/union or non-union false joint (pseudoarthrosis) 80 Regulation of Wound Healing The molecular basis Growth factor Epidermal growth factor (EGF) Sources Include activated macrophages, salivary glands, keratinocytes Actions Mitogenic for keratinocytes and fibroblasts, stimulate keratinocyte migration and formation of granulation tissue Transforming growth factor α(TGF-α) Activated macrophages, keratinocyte and others Stimulates proliferation of hepatocytes and other epithelium Vascular endothelial growth factor (VEGF) Mesenchymal cells Stimulates endothelial proliferation, increases vascular permeability Platelet-derived growth factor (PDGF), Endothelial cells, smooth muscle cells, keratinocytes. Chemotactic for neutrophils, macrophages fibroblasts and smooth muscle stimulates proliferation of cells and extracellular matrix protein Fibroblast growth factors (FGFs) Macrophages, mast cells, endothelium and others mitogenic for fibroblasts stimulate angiogenesis and extracellular matrix protein synthesis Transforming growth factor β(TGF-β) Platelets, T lymphocytes, Chemotactic and mitogenic fibroblasts, macrophages, endothelial cells, stimulate angiogenesis and ECM protein keratinocyte, smooth muscle cells, synthesis fibroblasts Keratinocyte growth factor (KGF) (i.e.FGF-7) Fibroblasts Stimulates keratinocyte migration, proliferation and differentiation 81 Inflammation and healing Summary 1 Inflammation is a response to injury by a variety of agents. Acute inflammation → vascular changes and accumulation of neutrophils. Chronic inflammation → vascular proliferation and fibroblast formation producing fibrosis. These cell and tissue events are regulated by complex interactions involving many chemical mediators. 82 Inflammation and healing Summary 2 In healing wounds the process of acute and chronic inflammation are involved. Some specialised tissues can regenerate completely if their framework is preserved. Chemical mediators of inflammation are also implicated in wound healing. 83 General Pathology Lecture Inflammation and healing END 84 Inflammation and Healing 85 · Compare and contrast acute vs. chronic inflammation with respect to causes, nature of the inflammatory response and tissue changes · Describe the bodys response to cell injury, including the cellular and biochemical basis of inflammation and tissue healing · Describe the various ways in which the body can heal damaged or lost tissue, including how granulation tissue leads to scar tissue · Discuss the beneficial and harmful effects of inflammation Overview 86   Inflammation – body/tissue response to injury.  Acute:  Hours - few days.  Chronic:  Weeks - years. Healing – restoration of structure and function  Not always complete. Purpose of Inflammation 87 Generally “good”  Protect against injurious agents  Leads to recovery - healing. Can be excessive/inappropriate  Collateral tissue damage  Hypersensitivity reactions Inflammation 88 One of the very basic mechanisms of human disease 1. Congenital – prenatal 2. Trauma – physical injury 3. Inflammation – injury by harmful agents 4. Neoplasia – tumours 5. Degenerative – “falling apart” Terminology of Inflammation 89    Can affect every organ Latin or classical Greek organ name, followed by - (t) itis e.g. Hepatitis:  Hepar - liver  Inflammation - itis Skin Appendix Meninges Stomach Bronchus Sinuses Dermatitis Appendicitis Meningitis Gastritis Bronchitis Sinusitis Bladder Liver Kidney Colon Pleura Lung Cystitis Hepatitis Nephritis Colitis Pleuritis Pneumonia Acute Inflammation – Gross 90    Local features recognizable with naked eye  Skin, subcutaneous tissue  Internal organs – intra-operatively +/- Systemic response  Malaise - feel sick  Pyrexia – fever  Changes in blood e.g. increased white cell count (leucocytosis) and changes to proteins +/- Localising signs  e.g. Pain in right iliac fossa in acute appendicitis Acute Inflammation – Gross 91 Four principal changes described 2000 years ago  Redness  Swelling  Heat  Pain Plus  Loss of function First three changes – 2’ to blood vessel changes. Last two changes – 2’ to cause/consequence of injury. 92 Acute inflammation Acute Inflammation - Causes 93       Infections – micro-organisms: bacteria, viruses, fungi, parasites Toxins – exogenous chemicals or endogenous agents produced by organisms – e.g. gas gangrene Physical agents – trauma, thermal, radiation Foreign bodies – splinters, dirt, sutures – +/- physical, chemical, infectious components Ischaemia – e.g. dead cardiac muscle after coronary artery occlusion Immunological (hypersensitivity) reactions – misdirected Inflammation and infection - different! 94     Inflammation - tissue responses to injury Inflammation - many causes other than infection. Infection - presence of micro-organisms in/on tissue. Infection - can be without inflammation (colonisation) Acute inflammation - Microscopic 95  Vascular events:  ↑ blood vessel diameter and blood flow ◼ Dilation of arteries and capillaries  ↑ blood vessel permeability ◼ Mostly venules ◼ Leakage of fluid (oedema). ◼ Leakage of fibrin (exudate) ◼ Leakage of red blood cells (diapedesis) Acute inflammation - Microscopic 96  Cellular events - neutrophils from blood  Adhere to vessel walls (margination, rolling, adhesion)  Emigrate between endothelial cells  Move through injured tissue (chemotaxis)  Take up pathogens, dead cells (phagocytosis)  Sometimes different white blood cell  E.g. inflammation due to virus or autoimmune reaction - lymphocytes 97 Acute Inflammation – sub-types 98     Serous  large fluid volume  from plasma Fibrinous  severe injury  leakage of fibrinogen – activated to fibrin Suppurative  abundant neutrophils – mixed with dead cell/tissue debris = pus  abscess - localised collection of pus Ulcerative  defect on surface with tissue death Serous inflammation (skin blister) 99 Fibrinous pericarditis 100 Suppurative meningitis 101 Ulcerative gastritis (peptic ulcer) 102 Inflammation - Molecular events 103       Many chemically diverse mediators effecting above changes Different mediators can have similar effects, but at different stages A mediator can have variety of effects eg Pain and vasodilation. Pre-formed Synthesized after injury (usually) Plasma-derived Inflammatory Mediators 104 Pre-formed  Histamine, Serotonin (platelets, mast cells)  Vasodilation, ↑ permeability Newly synthesised  Prostaglandins – vosodilatation, pain, fever  Cytokines (e.g. TNF, IL-1) – chemotaxis, fever, appetite loss, ↑neutrophils  Nitric oxide – vasodilation, ↑permeability, chemotaxis Inflammatory Mediators 105 Plasma-derived  Kinins – generate vasoactive proteins  Complement – ↑permeability  Clotting factors –release other mediators from platelets, endothelium Others  Selectins and Integrins – adhesion molecules for margination and transmigraton of neutrophils in blood vessels Acute Inflammation 106  1. 2. 3. 4. 4 possible Outcomes Resolution Healing by scarring/fibrosis Progresses to chronic inflammation (Tissue destruction→ death) 107 Acute Inflammation – Outcomes 108  Complete resolution  Injuring agent and dead tissue eliminated  Vascular and cellular events reverse  Normal structure and function returned  Extensive tissue loss - death  Injuring agent cannot be overcome  Inflammation progressive  Tissue dies, then putrefies – gangrene  Vital organs and cardiovascular system overwhelmed by toxins  Septic shock - death Acute Inflammation - Outcomes 109  Healing by scarring Defect filled with dead tissue, neutrophils and exudate  In-growth of new blood vessels & fibroblasts = granulation tissue  This matures - ↓ blood vessels & cells, ↑ collagen = scar/fibrosis   Becomes chronic inflammation Persistent inflammatory response  +/- granulation tissue and fibrosis  110 Chronic Inflammation 111 Defined principally by duration ◼ Weeks, Months, Years (c.f. acute inflammation – hours, days) Chronic Inflammation 112  Following acute inflammation or chronic from outset  Persistent infections ◼ Low acute virulence e.g. Mycobacterium tuberculosis  Persistent toxins ◼ E.g. asbestos fibres in lung  Auto-immune diseases ◼ Inflammation against own antigens  Repetitive bouts of injury, inflammation and healing ◼ E.g. peptic ulcers Chronic inflammation - Gross 113   + Features of acute inflammation Effects of scarring  Deformity, contractures on skin ◼ E.g. after severe burns  Narrowing of hollow organs ◼ E.g. bowel in Crohn’s disease Chronic inflammation – Microscopic 114   Mix of tissue destruction (necrosis) and healing (scar) Inflammatory cells mostly “mononuclear” white blood cells  Macrophages: ingest pathogen and dead tissue, secrete mediators  Others: lymphocytes and plasma cells (auto-immune), eosinophils (hypersensitivity, parasitic), mast cells  Neutrophils in acute flare ups Chronic inflammation – Molecular 115    As in acute inflammation - complex interacting network of chemical mediators Many from macrophages or lymphocytes Again their chemistry and biology beyond the scope of this lecture Chronic inflammation – Subtypes 116   Non-specific – as above Granulomatous  In addition, aggregates of macrophages form granulomas  Often macrophages also fuse into multi-nucleated giant cells Tuberculosis 117 Chronic inflammation – Outcomes 118   Inactive  Acute elements subside  Affected area - scar Active  Persists and spreads – eventually may be fatal ◼ Extends progressively (e.g. pulmonary tuberculosis).  Persists but limited ◼ Chronic disability (e.g. osteoarthritis) Healing – Scar vs. Regeneration 119   Scar  Tissue defect replacement in organs incapable of regeneration Regeneration  Replacement by constituent cells  Tissue ‘framework’ still preserved  Normal structure largely restored Healing – Scar 120    As in wounds to skin and most internal organs Exceptions, e.g.  Brain necrosis  Bone fractures Three phases  Inflammation  Granulation tissue and re-growth of overlying epithelium  Collagen deposition, wound contraction and scar remodelling Healing by Primary Intention 121 Wound  Clean - uninfected  Limited tissue damage – surgical incision  Edges brought together – sutures  Filled with small amount of blood clot – scab Healing by Primary Intention 122 