Lecture W1 Inflammation and Soft Tissue Healing PDF

Inflammation and its role in tissue healing and chronic disease Brooke Coombes [email protected] Griffith University acknowledges the people who are the traditional custodians of the land, pays respect to the Elders, past and present, and extends that respect to other Aboriginal and Torre...

Inflammation and its role in tissue healing and chronic disease Brooke Coombes [email protected] Griffith University acknowledges the people who are the traditional custodians of the land, pays respect to the Elders, past and present, and extends that respect to other Aboriginal and Torres Strait Islander peoples. What do these have in common? What about these… Learning outcomes 1. Describe and compare the pathophysiology and presentation of acute and chronic inflammation 2. Describe the process of soft tissue injury and healing 3. Identify factors and treatments that influence soft tissue healing What causes inflammation? • Inflammation is triggered when the cells that make up tissues are injured or die. It may be due to: • Infections • Physical injury - blunt trauma, traction, cuts • Heat, cold, chemicals, radiation, UV light • Foreign bodies • The body’s defense system can also attack its own tissues What are the outcomes of inflammation? In many circumstances, inflammation is • Rapid (commences within minutes) • Destroys pathogens, removes dead cells • Regulates tissue regeneration or repair following injury • Then dissipates within few hours to days (short lived) Regeneration Cell damage Acute inflammation Healing Repair by scar What are the outcomes of inflammation? Cell damage Acute inflammation Chronic inflammation Healing Tissue destruction & attempts at healing In some circumstances, inflammation may linger for months to years • E.g. Immune system may fail to eliminate pathogen Inflammation can alo be activated when no apparent injury or disease • Body attacks nearby health tissue How does our immune system function? Innate immune response • 1st line of defense • Fast – responds within hours • System you are born with • Specific stimulus will elicit essentially identical responses • Regulates tissue repair following injury Adaptive immune responses • Takes more time to develop (responds in days) • Responses vary greatly between individuals • Can become maladaptive – eg in autoimmune conditions How does our immune system function? Innate immune response • 1st line of defense • Fast – responds within hours • System you are born with • Specific stimulus will elicit essentially identical responses • Regulates tissue repair following injury Adaptive immune responses • Takes more time to develop (responds in days) • Responses vary greatly between individuals • Can become maladaptive – eg in autoimmune conditions Immune system “players” Deficiency or dysfunction of our immune system can lead to: • Excessive responses e.g. hypersensitivity diseases • Reactions against own cells/tissues e.g. autoimmune diseases Local responses of acute inflammation 5 cardinal features of acute inflammation Systemic responses of acute inflammation • Fever, delirium, hypotension, hypovolaemia, tissue oedema • Septic shock can result in • cardiovascular collapse • acute respiratory distress syndrome • disseminated intravascular coagulation • multi-organ failure and often death Davidson 2018 Is all inflammation the same? Acute inflammation • Features – Week 1 • Vascular changes –red, warm, swollen • Pain & dysfunction • Classic inflammatory cells (predominantly neutrophils) • History –onset and resolution Week 3 Is all inflammation the same? Chronic inflammation • Features – • Tissue destruction + attempts at healing • Angiogenesis –proliferation of small blood vessels • Fibrosis • Chronic inflammatory cells (macrophages, lymphocytes) • History –months to years (not short lived) Is all inflammation the same? Chronic inflammation 2404AHS Inflammation and joint pain • Inflammation isn’t the cardinal feature of all types of arthritis • Rheumatoid arthritis is a chronic, progressive autoimmune disease marked by systemic inflammation • Immune system initiates an attack against healthy tissue • Osteoarthritis is caused by degeneration of cartilage, which can irritate surrounding soft tissues and cause low grade local inflammation Week 2 https://roberthowells.com.au/ Inflammation and cardiovascular disease • Buildup of fatty, cholesterol-laden plaque inside arteries (atherosclerosis) • LDL (bad) cholesterol causes chronic inflammation of vessel wall • Build up of cell debris à thickening, narrowing and stiffening of artery walls à inadequate blood flow to heart or legs à angina or intermittent claudication • Debris can break off à heart attack Week 10 Inflammation and diabetes & obesity • Diabetes promotes oxidative stress which enhances inflammation Week 11 • Visceral fat (fat that accumulates around waist) contains macrophages++ and proinflammatory cytokines à low grade inflammation • Obesity increases the risk of heart disease, diabetes, osteoarthritis and tendinopathy Drjockers.com Inflammation and respiratory conditions Asthma • Is an inflammatory disease of the airways • Can be triggered by exposure to dust, smoke or viral infection Week 12 Covid-19 sequelae • Systemic inflammation thought to underpin cardiac and respiratory failure Akhmerov Circulation Research. 2020 Measurement of inflammation in blood • • C-Reactive Protein (CRP) is the most widely used lab measure of inflammation • CRP is produced by liver cells in response to acute inflammation • CRP increases within 6hrs of stimulus and falls quickly once stimulus is removed High sensitivity CRP used to measure low levels of inflammation • • • Hs-CRP is used to measure risk of heart disease and stroke Erythrocyte Sedimentation Rate (ESR) is an indirect measure of inflammation • ESR levels increase at a slow rate in response to inflammation • ESR can take weeks to return to normal levels Patients with high ESR but normal CRP may have systemic inflammatory or autoimmune processes Davidson 2018 Soft tissue injury and healing Soft tissue healing 1) What are the 3 stages 2) What is the purpose of each stage 3) What are the symptoms Stages in soft-tissue healing • 3 (or 4) overlapping phases • Rehabilitation should be matched to the appropriate stage of healing Stages in soft-tissue healing • Bleeding & haemostasis • Haemostasis is the natural process that stops blood loss • Involves vasoconstriction (blood vessels narrow), platelet plug formation (platelets adhere into plug to block blood flow) and coagulation (fibrin mesh is formed to hold the platelet plug together) • Once blood flow has ceased, tissue repair can begin • The amount of bleeding can influence subsequent healing Stages in soft-tissue healing • Stage 1 - Inflammatory • Inflammation occurs within the first 1-2 hours after injury, peaks at around 1-3 days, and generally lasts for a couple of weeks • Inflammatory cells & mediators released • Vasodilation • Chemical sensitisation of nerve endings • Phagocytes eliminate debris Redness, warmth, swelling, pain, loss of function (poor tissue strength) Stages in soft-tissue healing • Stage 2 - Proliferative phase • Cells and proteins needed to create new replacement tissue or scar tissue are generated • Starts within 24-48 hours, peaks at around 2-3 weeks after injury and stops after around 4-6 months • Various cell types (differentiation) • e.g. fibroblasts proliferate and lay down collagen; • myoblasts proliferate and form myofibres (muscle fibres) • New blood vessels form (angiogenesis) Pink, soft, granular appearance Tissue is thicker but weak Stage in soft-tissue healing • Stage 3 - Remodeling (or maturation) phase • New tissue is not good quality or very functional • Remodeling begins 2-3 weeks after injury and continues for months to years • Tissue is reorganized & oriented along lines of stress • cross linking of collagen, type of collagen • Scar tissue contracts, tissue returns to normal thickness • Tissue strength increases Tissue becomes less thick, function improves Ligament Rec reading: Montgomery et al 1989 What causes a ligament injury? • MOI – Commonly from sudden stretch in awkward joint posture • Can result in partial or full thickness tear Ligament healing • 3 major factors influence ligament healing 1. Gap between ligament ends (e.g. surgical repair may be needed in full thickness tear) 2. Location of injury (ACL – poor healing capacity) 3. Mobilisation vs immobilization of injured tissue Ligament injury Frank 1983 Muscle Rec reading: Montgomery et al 1989 What causes a muscle injury? MOI include • Laceration • Contusion (sudden compressive force/blow) • Sudden muscle contraction or traction • Unaccustomed overload Classification of muscle strains & ruptures • Can be clinically classified • Grade I - tear of only a few muscle fibers (minimal haematoma), pain & spasm, minimal loss of function • Grade II – greater muscle/fascia damage (greater haematoma), clear loss of function • Grade III– complete rupture, major or complete loss of function • MRI can accurately confirm/rule out muscle injury Jarvinen 2005 Muscle injury Proliferative phase • Myoblasts (cells that originate from satellite cells & mononuclear leukocytes) proliferate and fuse with viable ends of existing myofibres to fill the gap • Myoblasts develop into striated myofibres, nuclei alignment occurs • Vascular ingrowth occurs to revascularize tissue (angiogenesis) • Re-innervation of muscle fibres occurs (required for sensory & motor function of the muscle) Remodeling phase • Myofibres mature • Reorganization and orientation of regenerating myofibres • Formation of cross-links Jarvinen 2005 Muscle injury • 5 major factors that influence muscle healing 1. Source of myofibres 2. Adequate vascularization 3. Adequate innervation 4. Extracellular matrix 5. Limited early stress across the wound Regeneration Scar formation • Intact extracellular matrix • Massive gap between tissue ends (scaffolds & helps fibres to • Tissue ischaemia achieve proper orientation) • Gross nerve damage (unable to reinnervate) • Appropriate stress – early motion promotes parallel orientation of • Inappropriate timing of stress or motion during healing fibres • Too much load promotes excessive granulation tissue formation Location of muscle strain/tear • Muscle https://www.sportsinjurybulletin.com/hamstring-injuries-whylocation-and-anatomy-matters/ Muscle contusion • Muscle contusions undergo a similar healing process to strains/ruptures • Time frames shorter for contusion Jarvinen 2005 Delayed onset muscle soreness (DOMS) • Unaccustomed or excessive activity (often eccentric activity) causes microdamage of actin and myosin cross-bridges • Inflammation can be measured in blood eg creatine kinase • Nociceptors are stimulated – pain + stiffness Delayed onset muscle soreness (DOMS) • Muscle soreness starts after 24 hrs, peaks at 24-48 hrs and subsides by 7 days • Stiffness, reduced ROM & strength Compartment syndrome • Increased pressure due to oedema, haemorrhage in a confined space causes ischaemia of muscle tissue • Nerve conduction is impaired/blocked • Swollen, painful limb, tense muscle, • May have weak pulse or diminished nerve function Jarvinen 2005 Deep venous thrombosis (DVT) • Can mimic a muscle injury • Clot in deep veins • Causes include surgery, trauma, prolonged rest e.g. flights, clotting disorders • Clot can dislodge and travel to lungs • Swollen, red, painful limb, tense muscle Complications of muscle injury • Myositis ossificans • Proliferation of bone and cartilage within skeletal muscle • Typically occurs weeks after major trauma • Tissue necrosis e.g. if large haematoma Tendon Rec reading: Montgomery et al 1989 What causes a tendon injury? • Often chronic overload & microdamage • Can rupture from high force e.g. biceps Chronic tendinopathy • Features of chronic (non-resolving) inflammation • Chronic inflammatory cells • Tissue destruction + attempts at healing • Angiogenesis –proliferation of small blood vessels • Fibrosis • Tendon is thicker, disorganized collagen, neovessels present, weaker mechanical properties Dakin BMJ 2018 Tendinopathy Healthy tendon Tendinopathy Nerve Davidson’s Principles and Practice of Medicine Peripheral nerve injury - Classification Neurapraxia • Causes – local ischaemia, compression, traction, “Saturday night palsy” • Pathology – nerve conduction block but axonal continuity, no Wallerian degeneration • Recovery – complete (hrs-weeks) Peripheral nerve injury - Classification Axonotmesis • Causes – nerve crush injury • Pathology – division of axons, connective tissues may be intact or partially disrupted; Wallerian degeneration and regeneration • Recovery – weeks to months or may be incomplete Peripheral nerve injury - Classification Neurotmesis • Causes – nerve laceration • Pathology – division of entire nerve; Wallerian degeneration occurs; regeneration limited by intraneural damage and misdirected regeneration • Recovery –incomplete, months to years, Peripheral nerve healing • Inflammatory response, axon swells, breakdown of myelin, degradation of neurofilaments, phagocytosis of debris • Proliferation – Schwann cells and fibroblasts proliferate, Schwan cells (make the myelin) guide axon sprouting • Axonal regeneration occurs at a rate of almost 1 mm/day – hence moderate-severe injuries can take months to years to heal Treatment of acute inflammation & tissue injury Treatment of acute inflammation • Promote vasoconstriction to reduce bleeding, swelling & pain • Ice, compression, elevation • Protect from further injury • Immobilisation eg brace (for first few days) • Crutches & protected gait 3-7days Treatment of chronic inflammation • Treating chronic inflammation is more difficult • Regular exercise • Don’t smoke • Manage body weight • Fish oil (Omega-3 fatty acid supplements) Anti-inflammatory drugs Side effects of corticosteroids Treatment of tendinopathy by corticosteroids Helpful in 1st few weeks Harmful after 6-12 months Coombes et al, The Lancet 2010 Side effects of corticosteroids http://www.progressive-charlestown.com/ Side effects of NSAIDs https://www.verywellhealth.com Davidson 2018 Principals and practice of medicine Treatment of soft tissue injury by NSAIDs Disease-modifying anti-rheumatic drugs (DMARDS) • Alter the function of the immune system by suppressing inflammation • Use in first line for treatment of rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis • DMARDs can eliminate/reduce the need for NSAIDs or steroids Exercise Exercise • Exercise appears to reduce the proliferation of inflammation-promoting macrophages in fat tissue and promote release of anti-inflammatory proteins • Exercise can assist in weight loss • Exercise promotes tissue repair via increased vascularization, cellular and extracellular proliferation and differentiation Immobilisation • Immobilisation after ligament injury has detrimental effects • lower ligament stiffness & ultimate strength • Increased resorption of bone à increased risk of avulsion Woo et al Can you… 1. Describe and compare the pathophysiology and presentation of acute and chronic inflammation 2. Identify factors that influence soft tissue healing 3. Compare and contrast the management of soft tissue injury at different stages of healing References • Understanding inflammation – Harvard Health Guide • Davidson’s Principles and Practice of Medicine 23rd Edition Ralston (Ed) Elsevier Edinburgh • Montogmery et al 1989 Healing of Muscle, Ligaments and Tendons; Seminars in Vetinary Medicine and Surgery Vol4(4), p304-311