HENT Pathophysiology PDF

HENT Pathophysiology Robert Beach, M.D. Oral Cavity Caries Gingivitis Periodontitis Apthous ulcers Herpes simplex Candida Pharyngitis-viral, Streptococcus Epiglottitis-Hemophilus influenza Croup-viral Leukoplakia Oral Cancer Tobacco use...

HENT Pathophysiology Robert Beach, M.D. Oral Cavity Caries Gingivitis Periodontitis Apthous ulcers Herpes simplex Candida Pharyngitis-viral, Streptococcus Epiglottitis-Hemophilus influenza Croup-viral Leukoplakia Oral Cancer Tobacco use HPV Nose/Sinuses Allergic rhinitis Infectious rhinitis-adenovirus Sinusitis Allergic Viral Bacterial Fungal-mucormycosis Nasal polyps Granulomatous polyangiitis-Wegener’s granulomatosis Nasopharyngeal carcinoma-EBV Larynx Laryngitis Vocal Cords Nodules Singer’s cords Cancer-tobacco Ears Otitis externa Cholesteatoma Perforation Otitis media Obstruction/allergy Viral Bacterial Neck Brachial clefts Thyroglossal duct cyst Salivary Glands Sialadentitis Trauma Viral-mumps Bacterial-Staph aureus, Streptococcus viridans Auto-immune-Sjogren’s Ductal obstruction Tumors Warthin’s Tumor-benign Mucoepidermoid carcinoma Fusion geneMECT1:MAML2 increasing cAMP signaling and NOTCH protein expression  Ophthalmology 2024 MICHAEL B. WHITEHEAD DHSC, PA-C PHAS 5312 PATHOPHYSIOLOGIC PROCESSES I  Objectives Module I ARCPA Instructional Objective Ophthalmology B2.02c 1. Review the structures and function of the eye. 2. Outline the molecular events of light perception by the retinal cells. 3. Describe the common structural defects impairing vision: hyperopia, presbyopia, myopia, astigmatism, amblyopia, and nystagmus. 4. Discuss how vitreous fluid forms and complications of imbalance in production and removal. 5. Explain how intraocular pressure may become elevated and how it may affect vision. 6. List common conditions of the cornea, lens, conjunctiva, and eyelids. 7. Describe retinal changes of diabetic retinopathy, hypertensive retinopathy, and macular degeneration.  Topics  Anatomy of the eye  Vitreous humor  Common conditions  Cornea  Lens  Conjunctiva  Eyelids  Changes from  Diabetic retinopathy  Hypertensive retinopathy  Macular degeneration  Anterior Chamber  Anterior border is the cornea  Lateral borders are trabecular meshwork  Posterior border is the iris  Posterior Chamber 5  Small chamber behind the iris (smaller than the anterior chamber)  Anterior border is the posterior iris  Posterior border is the lens  Contains the ciliary body  The ciliary body produces aqueous fluid which fills the posterior chamber and enters the anterior chamber through the pupil.  Vitreous Humor  Produced by cells of the ciliary body  Embryonic cells that degenerate post-birth  Fixed amount of fluid  Helps maintain shape of globe  Gel–like consistency  Changes with aging  Floaters  Retinal detachment  Retinal Cells & Light Perception  Retina is innermost layer  Cells convert light energy into 3D images  Only extension of the brain viewed from the outside  Extension of Optic nerve (CN II)  Light reaches photoreceptor cells>rods and cones>action potentials conveyed to the brain>optic chiasm>lateral geniculate nucleus>visual cortex  Development begins during 4th week of embryogenesis continues into the first year of life  Consumes a high amount of oxygen  Six different cell lines that divide into 10 layers  Cornea  Major refractive surface  Avascular  Aids transparency  Contributes to low incidence of graft rejection  Corneal Degenerations  Unilateral or bilateral – usually non-familial  Band keratopathies  Calcific band keratopathy  Ca deposits in the Bowman layer (anterior)  Actinic band keratopathy  Exposure to chronic levels of UV light  Keratoconus – progressive corneal thinning  Cornea changes shape – becomes conical  Associated with Down Syndrome, Marfan Syndrome, and atopic disorders  Corneal Dystrophies  Generally inherited  Fuchs Endothelial Dystrophy  Loss of endothelial cells  Edema and thickening of the stroma  Stromal Dystrophies  Stromal deposits create opacities  Loss of vision  Glaucoma  Distinctive changes in visual fields and cup of the optic nerve  Second leading cause of blindness  Elevated intraocular pressure (IOP)  Normal IOP 8-21 mmHg  Can have both primary and secondary causes  Some primary causes are genetic  Myocillin (MYOC) and optineurin (OPTN) genes  Open angle glaucoma  Flow of aqueous maintained  Change in resistance  Too much aqueous  Poor drainage system  More prevalent in patients of European or African descent  Closed angle glaucoma  Emergency condition  Rapid rise in IOP  Peripheral iris adheres to trabecular network  Blocks passage of aqueous humor  Occurs in patients with shallow anterior chambers  More prevalent in patients of Asian and Inuit descent  Risk factors  FH, 60+, female, hyperopia, medications, flaky deposits (pseudoexfoliation), race  Presentation Closed Angle Glaucoma  Symptoms:  Decreased vision  Halos around lights  Headache  Severe eye pain  Nausea and vomiting  Presentation Closed Angle Glaucoma  Signs:  Conjunctival redness  Corneal edema or cloudiness  A shallow anterior chamber  A mid-dilated pupil (4 to 6 mm) that reacts poorly to light Acute angle closure glaucoma  Lens  Closed epithelial system  Capsule (basement membrane) envelops the lens  Bathed by aqueous humor – circulates via pupil from posterior to anterior chamber  Cataracts  Opacification of the intraocular lens  Most common worldwide cause of reversible blindness  50% of patients with blindness in developing countries  5% of patients with blindness in developed countries  Can be congenital or acquired  Etiology / Risk Factors  Aging most common reason  Diabetes Mellitus  Smoking  Eye trauma  Corticosteroid use  Some psychotropic meds  Age Related Classification  Nuclear cataract  Lens may have yellow appearance  Progresses slowly – may not affect vision until later in the process  Cortical cataract  Vision not affected unless the visual axis or most/all of the cortex is involved  Lens may have a white and milky appearance  Posterior subcapsular cataract  May affect younger patients  May cause glare  May reduce near vision more than distance  Presentation History (Nuclear)  Usually slow and progressive loss of visual acuity  Glare and haloes from lights  Double vision or ghosting  Often asymmetrical  Reduced color intensity  Challenges recognizing faces or small distant objects  Often intact near vision Nuclear Nuclear Nuclear  Uveitis  Uvea consists of the iris, choroid, and ciliary body  Uveitis – inflammation of one or more tissues of the uvea  Iritis is anterior uveitis  Cause may be local or systemic  JRA, sarcoidosis, Pneumocystis carinii, autoimmune  Uveitis – infectious causes  Herpes virus  Keratouveitis can involve the cornea (anterior)  Cytomegalovirus (CMV)  Posterior most often  Usually found in immunocompromised pts (HIV)  Toxoplasmosis  May be reactivation of congenital acquisition  Other causes  Syphillis, TB, cat-scratch, West Nile, Ebola, Zika  Uveitis – inflammatory causes  Spondyloarthritis (SpA)  Ankylosing spondylitis / reactive arthritis (HLA-B27)  20-40% develop anterior uveitis  Typically unilateral  Sarcoidosis  ~20% present with eye sx as initial presentation  Juvenile idiopathic arthritis (JIA)  Usually between ages of 2-8  Usually bilateral with slow onset  Psoriatic arthritis and IBD  Often have a SpA component  Uveitis – usually restricted to the eye  Post-traumatic (including surgery)  Idiopathic  Subconjunctival Hemorrhage  Common in elderly (>80 y/o) with systemic dz  In 5 years Neovascularization Neovascularization Retinal Detachment Retinal Detachment  Nonproliferative Retinopathy (NPDR)  Variable appearance of:  Nerve-fiber layer infarcts (cotton wool spots)  Intraretinal hemorrhages  Hard exudates  Microvascular abnormalities (microaneurysms, occluded vessels, and dilated or tortuous vessels)  Vision loss secondary to macular edema  Categorized into mild, moderate, severe, and very severe Retinal hemorrhage and microaneurysms  Hypertensive retinopathy  Severe forms of HTN create both acute and ongoing target organ damage (including eyes, kidneys, and hypertensive encephalopathy)  Increasing retinal microvascular changes  Mechanisms:  Arterial and arteriolar vasoconstriction as compensation for increased pressure  When BP is too high or sustained, autoregulation fails  Rising pressure damages vascular walls  When vasodilation occurs, can lead to cerebral edema  HTN retinopathy usually associated with diastolic BP of >120mmHg  Expect neuro sx as well  Hypertensive retinopathy  Classifications  Mild – Retinal arteriolar narrowing related to vasospasm, arteriolar wall thickening or opacification, and arteriovenous nicking, referred to as "nipping".  Moderate – Hemorrhages, either flame or dot-shaped, cotton- wool spots, hard exudates, and microaneurysms.  Severe – Some or all of the above, plus optic disc edema. The presence of papilledema mandates rapid lowering of the blood pressure. Copyrights apply  Age-related Macular Degeneration (AMD)  Degenerative dz of central portion of retina (macula)  Loss of central vision  Leading cause of blindness  Affects many ADLs  Classifications:  Dry (atrophic)  Wet (neovascular or exudative)  Pathogenesis unclear Copyrights apply  Dry AMD  Early lesions more common  Findings may include:  Drusen  Localized deposits of extracellular material  Can be hard, soft, or crystalline and calcific  Progression to advanced AMD increases with amount of soft drusen  Geographic atrophy of the retinal pigment epithelium  Thinning and loss of tissue in the macula  Pigment epithelial detachments  Subretinal pigment epithelial clumping  Wet AMD  More common than dry in advanced AMD  Large soft drusen or pigmentary clumping increases risk of Wet AMD  References  American Academy of Ophthalmology - https://www.aao.org/eye-health/diseases/what-are- cataracts  Dynamed - Cataracts in Adults  Robbins and Coltran. Pathologic Basis of Disease. 9th ed. Ch. 29  Up To Date  https://collections.lib.utah.edu/ark:/87278/s68d2ss q  https://www.ncbi.nlm.nih.gov/books/NBK545310/ Structure, Function, and Disorders of the Integument Prof. Paul Shreve, MPAS, PA-C Pathophysiologic Processes I Fall 2024  Objectives Describe the pathophysiologic basis for changes in color, surface texture, swelling, temperature, and sensitivity of the skin (LO-A) Apply knowledge of the anatomic and immunologic structure of the skin to discuss the role of the skin in protecting against direct invasion of the skin and appendages by pathogens (LO-A) Explain the anatomic basis for the skin as a barrier and the role of normal flora that colonize the skin in this function (LO-A) Distinguish between common skin lesions or infections and their underlying pathophysiologic cause (immunologic, inflammatory, bacterial, viral, fungal, parasitic, exogenous) (LO-A) Apply knowledge of the molecular basis of neoplasia to an understanding of the clinical presentation, biologic behavior, morphologic appearance, classification, diagnosis, prognosis, and therapy of benign and malignant skin neoplasms (LO-A) Explain the role of ultraviolet light and other environmental factors in the development of various skin cancers (LO-A)  Clinical Manifestations of Skin Abnormalities Macule Vesicle Keloid Papule Bulla Scar Patch Pustule Excoriation Plaque Cyst Fissure Wheal Telangiectasia Erosion Nodule Scale Ulcer Tumor Lichenification Atrophy  Pathophysiology Atrophy Hyperplasias Dysplasias Neoplasias Genetic factors Inflammation – Immunologic – Infection-viral, bacterial, fungal Physical injury – Burns – Pressure ulcers – Toxic exposures  Disorders of Pigmentation & Melanocytes Freckle Caused by a focal abnormality in pigment production, enhanced melanin transfer to keratinocytes, or a combination of both Lentigo Benign localized hyperplasia of melanocytes Freckles Lentigo  Melanocytic Nevus (Pigmented Nevus, Mole) Caused by acquired activating mutations in components of the RAS signaling pathway Pathogenesis Types of Melanocytic Nevi Nevus Variant Diagnostic Cytologic Features Clinical Significance Architectural Features Congenital nevus Deep dermal and Identical to ordinary Present at birth; sometimes acquired nevi large variants have subcutaneous increased melanoma growth around risk adnexa, neurovascular bundles, and blood vessel walls Blue nevus Non-nested dermal Highly dendritic, Black-blue nodule; infiltration, often heavily pigmented often confused with with associated nevus cells melanoma clinically fibrosis Spindle and Fascicular growth Large, plump cells Common in children; epithelioid cell with pink-blue red-pink nodule; nevus (Spitz nevus) cytoplasm; fusiform often confused with cells hemangioma clinically Halo nevus Lymphocytic Identical to ordinary Host immune infiltration acquired nevi response against surrounding nevus nevus cells and cells surrounding normal melanocytes Dysplastic nevus Coalescent Cytologic atypia Potential marker or intraepidermal nests precursor of melanoma Congenital Nevus Blue Nevus Spindle & Epithelioid Cell Nevus (Spitz Nevus) Halo Nevus  Dysplastic Nevi Can be direct precursors of melanoma Caused by acquired activating mutations in NRAS and BRAF genes as well as increased CDK4 activity Dysplastic Nevus  Melanoma Caused by acquired mutations caused by exposure to UV radiation Most frequent driver mutations affect cell cycle control, pro-growth pathways, and telomerase  Melanoma Mutations affecting cell cycle control Mutation of CDKN2A gene causing decreased production of P15, P16, and ARF Normally, CDKN2A encodes p15, p16, and ADP- ribosylation Factor (ARF) P16 inhibits CDK4 and CDK6 allowing retinoblastoma (RB) tumor suppressor to block cells in G1 phase ARF enhances activity of p53 by inhibiting MDM2 (stimulates p53 degradation)  Melanoma Mutations affecting pro-growth signaling pathways Aberrant increases in RAS and PI3K/AKT signaling promote cell growth and survival Melanoma  Melanoma Mutations that activate telomerase Mutations of TERT gene encodes the catalytic subunit of telomerase This results in upregulation of telomerase resulting in immortality of the cells due to constant addition of telomeres at the terminal ends of chromosomes Melanoma  Benign Epithelial Tumors Seborrheic Keratosis Activating mutations in fibroblast growth receptor factor-3 (FGFR3) drive the growth of the tumor Seborrheic Keratosis  Acanthosis Nigricans Important cutaneous sign of underlying benign and malignant conditions (Type II diabetes mellitus & gastrointestinal adenocarcinoma) Disturbance leading to increased growth factor receptor signaling Familial form is associated with germline activating mutations in FGFR3 In type 2 diabetes, hyperinsulinemia increases stimulation of insulin-like growth factor receptor-1 (IFGR1) In paraneoplastic acanthosis nigricans cause is uncertain but has been linked to high levels of TGF-α Acanthosis Nigricans  Premalignant & Malignant Epidermal Tumors Actinic keratosis Hyperkeratosis in sun-damaged skin Superficial dermis contains thickened elastic fibers Likely a result of abnormal elastic fiber synthesis by sun- damaged fibroblasts Actinic Keratosis  Squamous Cell Carcinoma Caused by DNA damage from exposure to UV light affecting the function of p53 p53 affects cells in the G1 phase and promotes either DNA repair or elimination of cells damaged beyond repair When protective functions of p53 are lost DNA damage from UV light is repaired by mechanisms prone to error leading to mutations that are passed to daughter cells Squamous Cell Carcinoma  Basal Cell Carcinoma Aggressive cutaneous tumor caused by mutations that activate the Hedgehog signaling pathway Associated with UV light exposure Can be locally invasive Basal Cell Carcinoma Basal Cell Carcinoma  Acute Inflammatory Dermatoses Urticaria Result of antigen-induced release of vasoactive mediators (histamine) from mast cells Mast cell-dependent, IgE-dependent Occurs following exposure to antigen means induced by an allergen (pollens, foods, drugs, insect venom) and is anexample of a localized immediate hypersensitivity (typeI) reaction triggered by the binding of antigen to IgEantibodies that are attached to mast cells through Fc receptors Mast cell-dependent, IgE-independent Results from substances that directly incite degranulation of mast cells, no IgE involvement e.g abx, opiates, contrast media Mast cell-independent, IgE-independent Triggered by local factors increasing vascular permeability (like aspirin) Urticaria  Acute Eczematous Dermatitis Can be subdivided into: allergic contact dermatitis, atopic dermatitis, drug-related eczematous dermatitis, photoeczematous dermatitis, and primary irritant dermatitis Typically results from T cell-mediated inflammatory reactions (type IV hypersensitivity) Langerhans cells play a central role (especially in contact dermatitis) Acute Eczematous Dermatitis  Erythema Multiforme Self-limited hypersensitivity to certain infections and drugs Characterized by keratinocyte injury mediated by skin-homing CD8+ cytotoxic lymphocytes Erythema Multiforme Chronic Inflammatory Dermatoses Psoriasis Autoimmune chronic inflammatory dermatosis Appears to have an autoimmune basis Sensitized CD4+ Th1 and Th17 cells and CD8+ cytotoxic effector cells enter the skin and accumulate in the epidermis Psoriasis  Seborrheic Dermatitis Chronic inflammatory dermatitis Precise etiology is unknown Possible explanations include increased sebum production in response to androgens or an infection of certain fungal infections of the Malassezia genus Seborrheic Dermatitis  Lichen Planus Usually a self-limited disorder Commonly resolves spontaneously 1 to 2 years after onset Unknown pathogenesis Possibly an expression of altered androgens in basal epidermal cells or dermoepidermal junction causes a cell-mediated cytotoxic (CD8+) T-cell response Lichen Planus  Blistering (Bullous) Diseases Pemphigus Several forms exist, all are autoimmune Caused by IgG autoantibodies against desmogleins disrupting intercellular adhesions (difference is binding cells to cells) resulting in the formation of blisters Pemphigus  Bullous Pemphigoid Caused by antibody to bullous pemphigoid antigen (BPAG) – stabilizing protein in that binds the desmosomes to the laminar of the basement membrane. Prevents hemidesmosome from binding to basement membrane causing large blisters Bullous Pemphigoid  Disorders of Epidermal Appendages Acne vulgaris Pathogenesis not well understood 4 factors contribute to development Keratinization of lower portion of the follicular infundibulum and development of a keratin plug blocking sebum outflow Hypertrophy of sebaceous glands under the influence of androgens Lipase-synthesizing bacteria (Propionibacterium acnes) colonizing the upper and mid-portions of the hair follicle converting lipids to proinflammatory fatty acids Secondary inflammation of the involved follicle Acne  Rosacea Caused by high cutaneous levels of the antimicrobial peptide, cathelicidin (mediator of the cutaneous innate immune response) Rosacea  Infection Verrucae (Warts) Caused by human papillomaviruses (HPVs) Some are associated with a high risk for cancer (16 & 18) Produce E6 proteins that abolish p53 function Some are low risk (5 & 8 for example) Produce E6 proteins that don’t affect p53, rather interfere with Notch signaling Warts  Impetigo Caused by group A β-hemolytic Staphylococcus aureus Bacteria produces a toxin specifically cleaving desmoglein Impetigo  Sources Kumar V, Abbas A, Aster J. Robbins & Cotran Pathologic Basis of Disease. 10th ed. Canada. Elsevier Saunders; 2021  Physiology of Wound Healing Holly Goode, MPAS, PA-C Pathophysiology – Fall 2024 1. Differentiate regeneration from repair by fibrosis. 2. Describe the 5 stages of the cell cycle and how disruption of the cycle can lead to disease with resultant pathology. 3. Define labile, stable and permanent cells and discuss the relevance of each cell type with respect to turnover, repair and recovery of tissue following injury. Describe the steps in wound healing and scar Learning Objectives 4. tissue formation, including the role of key chemical mediators and cell types. 5. Understand multiple factors and different cell types in the stages of wound healing. 6. Contrast healing by primary, secondary, and tertiary intention. 7. Understand factors that influence outcome of wound healing and repair. 8. Describe potential complications in wound healing.  INTRODUCTION ❑ Injury to a tissue may result in cell death and tissue destruction. ❑ A wound is a disruption of the anatomic structure and function in any part of the body. ❑ Healing, on the other hand, is a cell response to injury in an attempt to restore the normal structure and function.  TISSUE HEALING ❑ Involves 2 distinct processes ▪ Regeneration ▪ Repair (scar formation) ❑ Dynamic balance between these two processes, depending on tissue type Inflammation and Repair Kumar, Vinay, MBBS, MD, FRCPath, Robbins & Cotran Pathologic Basis of Disease, Chapter 3, 71-113 Copyright © 2021 Copyright © 2021 by Elsevier, Inc. All rights reserved.  REGENERATION ❑ Replacement of lost or damaged cells with cells of the same type ▪ proliferation of residual cells ▪ development of mature cells from stem cells ❑ Complete restoration of the structure and function of the tissue is possible ❑ Limited capacity in mammalian tissue/cells: Salamander ▪ Unique cells within bone marrow, epidermis, intestine, and liver ▪ Hepatocytes ▪ Epithelial stem cells PROLIFERATION/ REGENERATION CAPACITY ❑Determines the ability of cells to heal themselves ❑ 3 groups of tissue ▪ Labile ▪ Stable ▪ Permanent  CELL CYCLE ❑Cell proliferation – controlled by the cell cycle & stimulated by growth factors and interactions of cells with the ECM ▪ Physiologic cell proliferation = repair ▪ Pathologic cell proliferation = cancer ❑Non-dividing cells are either in the cell cycle arrest in G1 or they exit the cycle to enter a phase called G0  LABILE TISSUES ❑ Continuously dividing/ proliferating ▪ Readily regenerate as long as pool of stem cells available ❑ Mitosis (M) – phase of cell cycle ❑ Examples: ▪ Hematopoietic cells in the bone marrow and lymphoid organs ▪ Epithelia of the gut, skin, cornea, respiratory tract, reproductive tract, and urinary tract STABLE TISSUES ❑ Quiescent (dormant) cells ❑ Minimal proliferative activity in their normal state → limited capacity/potential to regenerate following stimulus/ injury ❑ G0 phase of cell cycle ❑ Examples: ▪ Parenchyma of most solid tissues, such as liver, kidney, and pancreas ▪ Endothelial cells, fibroblasts, and smooth muscle cells  PERMANENT TISSUES ❑Terminally differentiated and non-proliferative → repair is dominated by scar formation ❑ Cell cycle is complete ❑ Examples: ▪ Neurons ▪ Myocytes ▪ Cardiac cells ▪ Skeletal  REPAIR/ SCAR FORMATION ❑Replacement of injured cells with connective (fibrous) tissue ❑Forms a patch to immediately re-establish both a physical and physiologic continuity to the injured organ ❑ Key players: ▪ cell types ▪ growth factors ▪ cytokines ▪ matrix proteins CELL TYPES  Growth Factors & Cytokines ❑ Secreted by certain cells of the immune system and have an effect on other cells ❑ Essential in tissue repair ❑ Actions: ▪ Stimulate cell division (mitosis) ▪ Involved in (growth) control – can stimulate or inhibit ▪ Protection from apoptotic death (survival) ▪ Stimulate migration, differentiation, angiogenesis, contractility, and fibrogenesis  Growth Factor/Cytokine Cell of Origin Function Platelet Derived Growth Factor Platelets Cell chemotaxis PDGF Macrophages Mitogenic for fibroblasts Endothelial cells Stimulates angiogenesis Stimulates wound contraction Transforming Growth Factor-alpha Macrophages Mitogenic for keratinocytes and TGF-alpha T lymphocytes Fibroblasts Keratinocytes Stimulates keratinocyte migration Transforming Growth Factor-beta Platelets Monocyte chemotaxis TGF-beta T lymphocytes Fibroblast migration & Macrophages Proliferation Endothelial cells Angiogenesis Keratinocytes Collagen & ECM synthesis Epidermal Growth Factor Platelets Mitogenic for keratinocytes and EGF Macrophages Fibroblasts Stimulates keratinocyte Migration Fibroblast growth factor Macrophages Chemotactic and mitogenic for Mast cells fibroblasts and keratinocytes T lymphocytes Stimulates angiogenesis Endothelial cells Fibroblast growth factor Fibroblasts Stimulates keratinocyte FGF migration, differentiation, and proliferation TNF Macrophages Activates macrophages Mast cells Mitogenic for fibroblasts T lymphocytes Stimulates angiogenesis Interleukin (IL)–1, IL-2, IL-6, and Macrophages IL-1 - Induces fever and IL-8 Mast cells adrenocorticotropic hormone Keratinocytes release, enhances TNF-alpha and Lymphocytes interferon (INF)–gamma, activates granulocytes and endothelial cells, and stimulates hematopoiesis IL-2 - Activates macrophages, T cells, natural killer cells, and lymphokine-activated killer cells; stimulates differentiation of activated B cells; stimulates proliferation of activated B and T cells; and induces fever IL-6 - Induces fever and enhances release Keratinocyte of acute- phase reactants by the liver IL-8 - Enhances neutrophil adherence, chemotaxis, and granule release INFs (IFN-alpha, -beta, and - Lymphocytes Activate macrophages delta) Fibroblasts Inhibit fibroblast proliferation Thromboxane A2 Destroyed wound cells Potent vasoconstrictor Stages of Wound Healing HEMOSTASIS INFLAMMATION Recall from Inflammation lecture  PROLIFERATION ❑ Occurs 3 – 21 days post injury ❑ Fibroblasts predominate ❑ 3 Distinct phases: ▪ Re-epithelialization ▪ Formation of granulation tissue by: Angiogenesis and Fibroplasia ▪ Extracellular Matrix (ECM) formation  RE - EPITHELIALIZATION ❑ Growth factors stimulate regrowth of the epidermis ❑ Epithelial cells divide and migrate across the healthy granulation tissue to form a barrier b/t the wound and the environment ❑ Keratinocytes are responsible for epithelialization  GRANULATION TISSUE ❑ Granulation tissue progressively fills the site of injury ❑ Primarily made up of: ▪ Fibroblasts ▪ Type III collagen ▪ New blood vessels ▪ Immune cells ❑ Essential intermediate tissue ▪ Body’s healing tissue ▪ Resistant to infection (macrophages/ antibodies)  E. ANGIOGENESIS Growth of new blood vessels into the wound which brings in O2 and nutrients  FIBROPLASIA ❑ Fibroblasts ▪ replicate/ proliferate/ migrate into wound ❑ Stimulated by cytokines and growth factors ▪ PDGF, FGF-2 and TGFβ ❑ Deposition of collagen ▪ migration and proliferation of fibroblasts into the site of injury ▪ lay down ground substance (ECM) proteins  EXTRACELLULAR MATRIX ❑ Exists as a scaffold to stabilize the physical structure of tissues ❑ Two forms of extracellular matrix: ▪ Interstitial matrix – present between cells ▪ Basement membrane – found between epithelium and mesenchymal cells  Functions of the ECM ❑ Mechanical support ▪ Anchorage, migration ❑ Control of growth ▪ Signals through cellular receptors – integrins ❑ Maintenance of cell differentiation ▪ Proteins affect degree of differentiation (fibronectin, vitronectin, thrombospondin) ❑ Scaffolding for tissue renewal ▪ Basement membrane needed for renewal of structure (stroma) ▪ Labile and stable cells depend on ECM to reestablish normal structure ❑ Storage of growth factors ▪ Allows for rapid response to injury and healing  COLLAGEN DEPOSITION ❑ Type I Collagen ▪ most common type (80 – 90% in adults – present in all tissues) ▪ primary collagen in a healed wound - secreted into the extracellular space → assemble into collagen fibrils → aggregate into larger, cable-like bundles called collagen fibers ❑ Type III Collagen ▪ predominates in newborns ▪ seen in early stages of wound healing Maturation/ Remodeling Phase ❑ Wound contraction ▪ Myofibroblasts – chains of fibroblasts (look like smooth muscle) ▪ Centripetal movement of wound edge towards center of the wound ❑ Collagen remodeling ▪ 3 weeks to 2+ years ▪ Number of intra- and intermolecular crosslinks b/t collagen fibers increases ▪ Type III decreases, replaced by Type I ▪ Tensile strength increases (70 - 80% of unwounded skin by 3 months)  Wound Closure Classification ❑ Primary ▪ All layers closed. ▪ Minimal scarring. ❑ Secondary Deep layers closed. Superficial layers left open to granulate from inside out. Prolonged healing requiring frequent wound care. Often leaves wide scar. ❑ Tertiary (Delayed Primary Intention) ❑Deep layers closed primarily. ❑Superficial layers left open until day 4. ❑Reinspection of wound: clean → irrigate and close. Infected → leave open to heal by 2° intention. Secondary Closure Tertiary Closure https://library.kissclipart.com/20181003/vqq/kissclipart-table-clipart-wound-healing-scar-9a65e081466f3870.jpg  Systemic Factors Inhibiting Wound Healing ❑ Infection ❑ Malnutrition ❑ Ischemia ❑ Vitamin deficiencies ▪ Circulation ▪ Vitamin C, Vitamin A ▪ Respiration ❑ Mineral deficiencies ▪ Local tension ▪ Zinc, Iron ❑ Immunocompromised ❑ Exogenous drugs ▪ HIV ▪ Doxorubicin (Adriamycin), ❑ Diabetes mellitus Gluco-corticosteroids ❑ Advanced age ❑ Ionizing radiation ❑ Smoking  COMPLICATIONS ❑ Deficient scar formation ❑ Excessive formation of repair components ❑ Exaggerated contraction  Deficient Scar Formation Dehiscence (rupture of wound) Ulceration (defect in the continuity)  Excessive Formation of Repair Components Keloid/ Hypertrophic Scarring Hypertrophic Granulation Tissue ▪ Excessive collagen (Type III vs Type I) ▪ Appears beefy, red ▪ Keloid scar – grows outside the boundaries of ▪ Prevents re-epithelialization the initial wound ▪ Hypertrophic scar – do not grow outside the boundaries of the initial wound  Exaggerated Contraction ❑ Deformation of surrounding tissue ❑ Can compromise the movement of joints ❑ Most common on: ▪ Palms/ soles ▪ Joints  References Gregory C. Sephel Stephen C. Woodward. Repair, Regeneration, and Fibrosis. Accessed online: http://downloads.lww.com/wolterskluwer_vitalstream_com/sample- content/9780781795166_Rubin/samples/91731_ch03.pdf Heather L. Orsted RN BN ET MSc David Keast MSc MD FCFP Louise ForestLalande RN MEd ET Marie Françoise Mégie MD. Basic Principles of Wound Healing. Wound Care Canada / Volume 9, Number 2 Robbins and Cotran Pathologic Basis of Disease. Ninth edition. Philadelphia, PA: Elsevier/Saunders, 2015.