Immune-Mediated Respiratory Tract Diseases Lecture PDF

https://medlineplus.gov/ency/images/ency/fullsize/19319.jpg Immune-Mediated Respiratory Tract Diseases viral infection chronic allergies Pollution, Irritants, Smoking Viral or Fungal URT Infections, Nasal Polyps, Asthma, COPD Dr. Shannon Murray, MS PhD BMS 5308 Lecture #38 [email protected]...

https://medlineplus.gov/ency/images/ency/fullsize/19319.jpg Immune-Mediated Respiratory Tract Diseases viral infection chronic allergies Pollution, Irritants, Smoking Viral or Fungal URT Infections, Nasal Polyps, Asthma, COPD Dr. Shannon Murray, MS PhD BMS 5308 Lecture #38 [email protected] Special Acknowledgement • This lecture has been given by Dr. Johnson and her acknowledgement is: • “Dr. Renee Prater to the OMS students for most of the 20 years that she taught at VCOM-VC. • I acknowledge her collegiality and experience as I have used parts of her slide set as inspiration for this lecture.” Lecture Objectives • Identify the normal architecture of the upper respiratory system. • Characterize elements of the anatomy, physiology, and immune system in the upper and lower respiratory system that contribute to the development of immune-mediated diseases • Identify the etiopathogeniesis, epidemiology, clinical manifestations, laboratory testing, differential diagnosis, treatment, and environmental control of: – The “common cold” and tracheitis – Rhinitis – Sinusitis – allergic and non-allergic – Otitis media • Define the pathophysiology of asthma and delineate the role of environmental and immunologic factors in the disease processes of asthma. • Identify the role of the role of the immune response in the development and pathogenesis of chronic obstructive pulmonary disease. • Describe the immunopathology of hypersensitivity pneumonitis and infer the strong association of hypersensitivity pneumonitis with specific occupations and exposures. • Apply the use of targeted immune therapy and personalized medicine to the treatment and management of immune-mediated respiratory disease. Reading References • Basic Immunology, 6th ed., Abbas, Lichtman, and Pillai – Chapter 11 – “Clinical Syndromes and Therapy" subsection of "Immediate Hypersensitivity" • Cellular and Molecular Immunology, 10th ed., Abbas, Lichtman, and Pillai – Chapter 20 – “Allergy” section Normal Architecture of the Upper Respiratory System Our URT is Colonized by Microbes “…a healthy adult breathes more than 7000 l of air a day, the upper respiratory tract (URT) is constantly bathed in airflow from the external environment…104–106 bacterial cells per cubic meter of air are inhaled per day…As a consequence, specific microenvironments in the URT harbor different microbial communities composed of variable proportions of resident and transient microorganisms [6].” What Causes Rhinitis and Sinusitis? What makes non-pathogenic URT microbes become pathogenic? The microbiome of the upper respiratory tract in health and disease Kumpitsch et al., 2019. BMC Biology The ‘Mucociliary Escalator’ Acts to Clear Microbes* from the URT Nasal Cavity & Lungs Pseudostratified ciliated columnar epithelium is first line of URT defense Turbinate and Upper Respiratory Tract Epithelium is Important in Immunological Defense: ‘Mucociliary Clearance’ • Pseudostratified ciliated columnar epithelium is first line of defense by beating in unison upwards in respiratory system: the “Mucociliary Escalator.” • Goblet cells are scattered throughout, use mucus to trap airborne particles >2-3 um. • Vascular plexus delivers immune cells to the nose and is an avenue to the lymphatics. Compromised Mucociliary Clearance Leads to Increased Susceptibility to Infections and Chronic Inflammatory Conditions Allergies Chronic inflammation including eosinophil ‘CharcotLeyden crystals’ Pollution, Irritants, Smoking 2o Bacterial Viral or Fungal URT Infections Nasal Polyps, Asthma, COPD Nasal Conchi (Turbinates) • • • • Long, narrow, curled bone shelf (shaped like seashell) Protrudes into the breathing passage of the nose Divides nasal airway into four groove-like air passages Lined by pseudostratified columnar ciliated respiratory epithelium with thick vascular and glandular tissue ‒ Inferior turbinates = largest, direct air flow, air conditioning ‒ Middle turbinates = smaller and project downwards toward the maxillary and ethmoid sinuses ‒ Superior turbinates = protect the olfactory bulb • Functions of the nasal conchi ‒ Direct airflow ‒ Humidify air ‒ Heat air ‒ Filter air Paranasal Sinuses • Air sinuses in the cranial bones • Four pairs of sinuses ‒ Maxillary – largest sinus, under eyes, in maxillary bone ‒ Frontal – superior to the eyes, in frontal bone ‒ Ethmoid – air cells in ethmoid bone between nose and eyes ‒ Sphenoid – sphenoid bone, center of skull base under pit • Functions of the sinuses ‒ Decreases weight of front of the skull/bones of the face. ‒ Increases resonance of the voice. ‒ Provides buffer against blows to the face. ‒ Insulates dental roots and eyes from temp fluctuations ‒ Humidifies, heats inhaled air ‒ Regulates intranasal and serum gas pressures ‒ Immunological defense Sinuses: important in human evolution? n i s a , t res e t n s, i e r v a i l t u a l c re rti a t s p e f s o o cl re r a u s o e s d an inu s s l n a a t n um fro h d n i n a d n u ar y o l f l i y x l a The m they are on orillas. es dg t n a a m i s r e p nze a p m i the ch Palatine Uvula Cleft palate may occur with bifurcated uvula • Conical projection from posterior middle soft palate • Composed of connective tissue, glands, muscle. • Articulation of guttural vocal sounds: German, French, Portuguese, Swedish, Celtic languages, not English). • Massaging the uvula causes gag reflex (piercing). • Abnormally long uvula can contribute to sleep apnea. • During swallowing the soft palate and uvula move superiorly to close off the nasopharynx, to prevent food from entering the nasal cavity. When this fails it is called nasal regurgitation and can contribute to upper respiratory tract infections (URTI). Auditory Tube (Eustachian tube, pharyngotympanic tube) 35 mm long, links nasopharynx to middle ear. Proximal 1/3 is bone, distal 2/3 is cartilage. Functions of the auditory tube: • Pressure equalization: normally closed but can pop open to let small amount of air through, to prevent damage to middle ear. Yawn, swallow, chew gum, or perform Valsalva maneuver to open the tube. • Upper airway infections and allergies can cause swelling of tube mucosa, trapping bacteria/fluid/mucus, causing infections. • Earaches and otitis media are more common in children because their tubes are shorter, smaller diameter, and more horizontal in orientation. Valsalva: moderately forceful exhalation against a closed airway, done by closing mouth, pinching nose shut while pressing out as if blowing up a balloon. Can test for cardiac function/ANS control of heart, or to "clear" ears, sinuses (equalizes pressure) with changes in ambient pressure in diving, hyperbaric oxygen therapy, or change in altitude. Increasing Susceptibility to Upper Respiratory Infection Conditions associated with increased risk of upper respiratory tract infection (URTI) • Seasonal allergies – pollen/allergens cause production of IgE, mast cell binding, histamine release, and clinical signs of hay fever • Smoking and pollution – cause mucus hypersecretion, chronic airflow obstruction, connective tissue damage, and squamous metaplasia of epithelium → diminished mucociliary escalator and impaired BALT immune function • IgA deficiency – most common immune deficiency disorder (1 in 700 people of European origin); inherited or drug-induced. May be asymptomatic or result in otitis media, conjunctivitis, bronchitis, sinusitis, pneumonia, etc. • Stress – alters hormonal, behavioral, and neural responses which collectively increase susceptibility to upper respiratory infections Common Cold or Rhinosinusitis • Definition – acute viral nasopharyngitis, highly contagious viral infection of URT ~ 1wk duration, usually in winter (living in close quarters) • Etiologies – RSV, AdV, parainfluenza virus, picorna-, corona-, or enterovirus; transmitted by aerosol, fomites, direct contact with secretions. • Symptoms – sore throat, runny nose, nasal congestion, sneezing, cough +/- muscle aches, fatigue, malaise, headache, loss of appetite • Pathogenesis – virus invades and damages resp mucosa and activates host immune response • Diagnosis – physical exam, symptoms • Treatment – self-limiting, so treat symptoms; no vaccines or antivirals are approved. (Some take mega-doses of vitamin C, echinacea, and/or zinc gluconate, but these are not approved by FDA.) https://i.natgeofe.com/n/2f073a22-ca86-487d-911a-335f8f7258ea/58222_2x3.jpg https://thenativeantigencompany.com/ products/respiratory-syncytial-virus-aglycoprotein-g-human-fc-tag-copy/ Some Viral Infections Impair Mucociliary Machinery and Increase Susceptibility to Secondary Infections Cilia destruction by SARS COV-2 infection in an in vitro human airway epithelial cell culture Robinot et al., 2021. Rhinitis • • • • Definition – irritated and inflamed nasal mucosal lining Affects about 20% of the population Etiologies – allergy, virus, bacteria, irritants Symptoms – sneezing, nasal congestion, nasal itching, rhinorrhea ‒ Ears, eyes, sinuses, and throat may also be involved ‒ Systemic effects – fatigue, somnolence, malaise due to acute phase response • Diagnosis – allergy tests, culture to rule out infectious cause • Treatment – antihistamines, leukotriene antagonists, CCS, decongestants, antibiotics • Pathophysiology ‒ Early phase response – increased mucus production, release of histamine, enzymes that cause connective tissue damage, leukotrienes, prostaglandin D2 due to IgE-mediated mast cell response to extrinsic protein ‒ Late phase response – eosinophils, lymphs, and macrophages respond later Etiology (Most Common) Rhinosinusitis ‘Common cold’, viral picornavirus, coronavirus, adenovirus, parainfluenza & others; ~0.5-2% get a 2obacterial infection** Rhinitis Allergies (AR) > Non-allergic (NAR) is due to pollution & irritants Sinusitis Otitis Media Tracheitis Key Features Symptoms Allergic Rhinitis Seasonal allergic rhinitis • Tree and flower pollen during March-April • Also, mold spores from fallen leaves in October-November Perennial allergic rhinitis • Can occur year-round from sensitivity to pet hair, mold on wallpaper, houseplants, carpeting, and upholstery Non-allergic rhinitis • Not IgE-mediated and not due to an allergic reaction; typically, the result of cigarette smoke or other irritants/pollutants; can be exacerbated by deviated septum, infections, over-use of OTC decongestants, etc. https://www.bernsteinallergyresearch.com/clinic/wp-content/uploads/sites/3/2021/03/AdobeStock_300511792.jpeg Mediators of Inflammation and Symptoms in Allergic Rhinitis • • • • • CD4 Th2 cells IgE-producing B cell Mast cell Eosinophil Basophil Key Cells • • • • • IL-4, IL-5, IL-13 IgE Histamine Prostaglandins Leukotrienes involved in Allergic Response https://step2.medbullets.com/ear-nose-throat/121791/allergic-rhinitis https://www.semanticscholar.org/paper/New-targets-forallergic-rhinitis-%E2%80%94-a-disease-of-HolgateBroide/d9c7d129f8d1b4678bec1bf5f89514c2e0a86593 Granulocytes Give Their Lives to Try To Kill the Extracellular Pathogen, Only it’s Not a Pathogen, it’s a piece of dog hair or pollen – a ‘sterile infection’! Anti-histamines 1o Allergic Response IgE binds Fc receptors on Mast Cells & Basophils Allergic Response Eosinophils try to kill the ‘invader’– at the expense of the tissue Complications of Allergic Rhinitis Eyes: allergic conjunctivitis Maxillary is the most infected sinus Besides the discomfort of allergic rhinitis, trapped fluid can result in secondary sinus infections; blocked auditory tubes may cause middle ear infections; lower airway involvement may result in asthma. 23 The Key: Allergen Avoidance • For outdoor seasonal allergies ‒ Stay indoors; close windows; use A/C rather than fans; use HEPA filter in bedroom ‒ Don’t hang laundry outside to dry ‒ Bathe/shower and change clothes after being outside • For year-round allergies ‒ Cover pillows and mattress with dust mite covers ‒ Remove carpet and install tile, hardwood, or area rugs ‒ Replace curtains with blinds ‒ Don’t sleep with your pets ‒ Use HEPA filter, air purifier in your bedroom ‒ Wash bedding and area rugs weekly with very hot water Immunotherapy for Allergic Rhinitis • Traditionally, allergen immunotherapy for treatment of allergic respiratory diseases has been administered through subcutaneous injections. ‒Weekly injections for 3-5 years to desensitize the patient ‒Induce isotype switch from IgE to IgG • Alternate approach – administer antigens orally, i.e., sublingually, as aqueous or liquid (glycerine) extract. Most successful with pollen, grass, dust mites > latex, food (still being studied). ‒Advantage – self-administered; lower risk of anaphylaxis or injection site infection. ‒Mechanism – antigens taken up by DCs in the mouth (fewer mast cells in the mouth), then presented to Th2 cells in draining LN, causing production of IgG4 ‒Ags that reach sm. intestine are taken up and presented to Th2 cells in Peyer’s patches → stimulates IgA production and development of peripheral tolerance Allergy Immunotherapy (AIT) Induced by High Dose Antigen Exposure Allergen sensitization Allergen immunotherapy (AIT) https://www.jacionline.org/article/S0091-6749(17)31665-2/fulltext Chronic Allergic Rhinitis Can Cause Nasal Polyps, Rhinosinusitis & Asthma CLCs are a key feature of severe asthma and chronic rhinosinusitis with nasal polyps https://www.science.org/doi/10.1126/science.aax6175 Nasal Polyps • Chronic rhinitis may cause sufficient irritation to cause polyp formation. • Polyps = 3-4 cm mass of edematous mucosa with loose stroma, hyperplastic or cystic mucous glands with mixed inflammation (neutrophils, eosinophils, plasma cells, lymphocytes) • May block airway and/or impair sinus drainage • Treatment – surgical removal http://www.pharmacology2000.com/Pulmonary /respiratory_anesthesiology/Polyps_1.jpg http://www.cityallergy.com/images/nasalpolypsthumb.jpg http://pathologyoutlines.com/caseofweek/200524image4.jpg Sinusitis • Definition: Inflammation of paranasal sinuses. • Etiologies: bacterial, fungal, viral, allergic, autoimmune • Acute (< 4 wk) – precipitated by earlier viral URT infection or allergies. Virally- or allergy-damaged surface tissues are then colonized by bacteria (Streptococcus/Haemophilus/Moraxella) • Chronic – (>12 wk) multifactorial origin, usually allergy, environmental (dust, pollution), bacterial/fungal infection (Staphylococcus). ~1- 5% of U.S. population. https://www.entcen tergr.com/wpcontent/uploads/20 15/04/sinus1.jpg • Symptoms: nasal congestion, facial pain/fullness, headache, fever, malaise, colored discharge, sometimes mistaken for a “toothache” • Maxillary sinusitis: pain/pressure in maxillary (cheek) area and mimics “toothache.” Most common sinus infected. • Frontal sinusitis: pain/pressure behind/above eyes, “headache”. • Ethmoid sinusitis: pain/pressure between/behind eyes, “headache”. • Sphenoid sinusitis: pain/pressure behind eyes, often refers back to vertex of head. https://www.stanfordchildrens.org/en/topic/default?id=sinusitis-in-children-90-P02063 Bacteria adhering to ciliated tissue removed from patient with chronic rhinosinusitis Fig. 3. Bacteria adhering to ciliated tissue removed from a patient with chronic rhinosinusitis. Cilia were stained with antibody for β-tubulin IV (green), and bacterial DNA was stained with DAPI (magenta). Confocal immunofluorescence slice was taken at ×60 as described previously (63). DOI: (10.1152/ajplung.00283.2020) Pathogenesis, Diagnosis, and Treatment of Sinusitis https://www.jacionline.org/article/S0091-6749(20)30113-5/fulltext • Pathology – resp. mucosa responds to stimulus (e.g., virus) → produces mucus and recruits inflammatory mediators → congestion, swelling, mucosal hyperplasia, blockage = an ideal environment for 2° bacterial growth • Diagnosis ‒ Allergy tests ‒ Culture of exudate ‒ CT scan (next slide) • Treatment ‒ Acute o Antihistamines, decongestants, analgesics o Nasal irrigation – neti pot o Antibiotics if symptoms persist >48 hours ‒ Chronic: o Nasal irrigation, surgery (e.g., FESS, balloon sinuplasty) https://www.trinityhealth.org/wp-content/uploads/2018/01/balloon.png Imaging in Sinusitis • Upper left: normal CT • Lower left: maxillary sinusitis • Upper right: maxillary and frontal sinusitis and osteomyelitis • Upper: normal CT of frontal sinus • Left: frontal sinusitis and osteomyelitis Etiology (Most Common) Rhinosinusitis ‘Common cold’, viral picornavirus, coronavirus, adenovirus, parainfluenza & others Rhinitis Allergies (AR) > Non-allergic (NAR) is due to pollution & irritants Sinusitis < Bacterial infection post-allergy or viral URTI Otitis Media Tracheitis Key Features Symptoms Sore throat, runny nose, congestion, cough, fatigue; symptomatic Tx IgE & granulocyte-mediated inflammation/tissue damage; antihistamines, leukotriene antagonists & decongestants; AIT via SCIT or SLIT Irritated/inflamed nasal mucosal lining; asthma; conjunctivitis Chronic: Nasal Polyps Otitis Media • Note anatomy of middle ear – located behind tympanic membrane (eardrum) and connected to pharynx via Eustachian tube (auditory tube). • Auditory tubes regulate pressure between middle ear and pharynx (“pops” with changes in altitude) • Children’s auditory tubes are smaller in diameter and more horizontally oriented than adults. • So, allergies or infections in pharynx/throat (viral or bacterial) can cause auditory tube to close, resulting in accumulation of edema, mucus, and inflammatory cells in the middle ear, causing otitis media. • Otitis media causes pain due to pressure on tympanic membrane (inflammation, edema, mucus, etc.). • Symptoms – pain, tugging at ear, irritability, hearing loss, loss of balance, fever, headache • Organisms – S. pneumoniae, H. influenzae, Moraxella catarrhalis, or several viruses • Treatment – antibiotics. Untreated middle ear infections can lead to tympanic membrane rupture. So, recurrent ear infections may require tubes to be placed in eardrum to relieve pressure and allow drainage from middle ear Tracheitis • Definition – infection/inflammation of trachea • Etiologies ‒ Usually bacterial after viral URTI (e.g., S. aureus) ‒ Or irritants – chlorine gas, sulfur dioxide, and dense smoke injure mucosa which makes the epithelium vulnerable to 2° infection ‒ Dangerous in young children – small diameter of trachea makes swelling/airway obstruction possible • Symptoms ‒ Deep cough, scratchy throat, fever ‒ Inspiratory stridor (crowing sign during inhalation) ‒ Chest pain, intercostal retractions Figure 1-10 – Basic Immunology, 6th ed., 2020 Pathology, Diagnosis, and Treatment of Tracheitis • Diagnosis ‒ Blood oxygen level ‒ Radiographs of chest (trachea) ‒ Nasopharyngeal/tracheal culture • Treatment ‒ Antibiotics ‒ Endotracheal tube if tracheal obstruction • Pathology – diffuse mucopurulent, necrotizing inflammation and acute airway obstruction at cricoid cartilage level, with subglottic edema Lower Respiratory Tract or Pulmonary Diseases https://training.seer.cancer.gov/images/anatomy/respiratory/bronchi_lungs.jpg • Dysregulated, hyperimmune responses that affect and damage the lung tissue, but not the upper airway • Affected people presumably have some genetic predisposition • Result in and due to inflammatory cellular infiltration of the lungs • Include a diverse set of diseases, but most can be classified into 2 subsets: ‒ Hypersensitivity reactions (types I, II, III, and IV) ‒ Eosinophilic reactions https://useruploads.socratic.org/fqXeQIqTzybYBn13dN9y_alveoli.jpg https://my.clevelandclinic.org/-/scassets/images/org/health/articles/6424-asthma Asthma • Group of immune-mediated diseases that end with increased bronchiole inflammation (with mucus production) and hyperresponsiveness of bronchial smooth muscle cells – both leading to airway obstruction ‒ About 70% due to IgE-mediated hypersensitivity response (T1HS) ‒ Remaining ~30% due to non-immune trigger (e.g., drugs, cold, exercise) with hypothesis that these conditions activate mast cell degranulation by alternative mechanism (e.g., local production of neurotransmitters) • Multifactorial disease with strong associations, but little mechanistic causality defined ‒ Family associations and suggestion of inheritance, but not Mendelian pattern ‒ Suggests multiple genes are involved – “polygenic inheritance” • Common triggers – dust mites, animal allergens, mold, resp. viruses, agricultural exposures (animal, silage), pollution, exercise, drugs, cold https://www.urmc.rochester.edu/MediaLibraries/URMCMedia/pulmonary/images/asthma-causes463.jpg Pathophysiology of Asthma • Sensitization – exposure, then induction of CD4 T cells ‒ Most often CD4 Th2 and B cells, leading to IgE production ‒ Some evidence for involvement of CD4 Th1, Th17, and Th9 in ongoing disease, esp. with airway remodeling and IL-17 • Early stage – re-exposure activates mast cells https://sphweb.bumc.bu.edu/otlt/MPHModules/PH/RespiratoryHealth/Asthma%20Flow%20Chart.png ‒ Leukotrienes cause vasodilation and bronchoconstriction ‒ Cytokines induce mucus and eosinophils ‒ Results in airway obstruction and symptoms • Ongoing or chronic disease ‒ Repeated cycles of recruitment and activation of eos and PMNs → tissue damage → tissue remodeling, fibrosis ‒ Repeated cycles of release of cytokines and mediators → smooth muscle hypertrophy → loss of elasticity Figure 20-9, Cellular and Molecular Immunology, Abbas, et. al., 10th ed., 2022 Mediators and Management of Asthma • Disease can be stratified into two subsets of severity ‒ “Low” and “high” based on biomarkers of eosinophilia (sputum and blood) and array of type 2 cytokines present in bronchial sample (BAL or biopsy) ‒ Stratification does not fully correlate with symptoms, but is a good predictor for responsiveness to immunotherapies • Management ‒ Two goals – 1) prevention and reversal of inflammation and 2) relaxation of smooth muscle cells ‒ Different sets of drugs to achieve each of 2 goals o Immunomodulators (e.g., corticosteroids) an immunotherapies (e.g., anti-IgE, anti-cytokine) for inflammation o Drugs that increase cAMP levels in smooth muscle cells to inhibit muscle contraction (e.g., β2-adrenergic agonists, antagonists of LTC4 receptor) Figure 20-10, Cellular and Molecular Immunology, Abbas, et. al., 10th ed., 2022 Hypersensitivity Pneumonitis • Presentation – cough, shortness of breath, fatigue that improves when triggers are avoided • Characteristics of disease ‒ Diffuse inflammation in bronchioles ‒ Mediated by T cells ‒ Triggered by inhalation of very small antigens o <3 µm in size o Over 200 identified (see notes) • Triggers ‒ Often environmental or occupational ‒ Animal matter, organic matter (e.g., silage, sawdust) bacteria, molds ‒ Can include drugs, esp. chemotherapeutics and some antibiotics, and chemicals (e.g., zinc) ‒ Smoking is NOT a risk factor, but may be protective – reduced rates and less severe https://www.sciencedirect.com/science/article/pii/S2531043718301120 Pathophysiology of Hypersensitivity Pneumonitis • Early disease caused by immune complex deposition in lung (T3HS) and CD4-produced cytokines (T4HS), but becomes T cell-dominated disease (T4HS) with repeated Ag exposure • Disease stages and mediators ‒ Sensitization – Ag inhaled into bronchioles and alveoli, activating resident APCs which induce IgG-producing B cells and CD4 Th1 cells ‒ On early re-exposures IgG and IgA bind Ag, and immune complexes deposited in basement membrane of bronchioles ‒ With continued re-exposures, o Memory CD4 Th1 cells are activated o CD8 T cells begin to be activated o IFN-γ is produced and macrophages are activated ‒ Chronic re-exposure leads to granuloma formation, fibrosis and, potentially with time, resp. failure https://www.sciencedirect.com/science/article/pii/S2531043718301120 Chronic Obstructive Pulmonary Disease (COPD) • Chronic and progressive disease • Inflammatory response alters lung physiology such that flow of air is inhibited • Presentation – asymptomatic to shortness of breath, persistent and productive cough, wheezing, fatigue, chest discomfort • A leading cause of morbidity and mortality globally • Two primary types ‒ Chronic bronchitis – excess inflammation and mucus production in bronchi ‒ Emphysema – breakdown of alveolar membranes • Triggers https://www.medicoverhospitals.in/diseases/copd-causes-risk-factors ‒ Globally, smoking is #1 risk factor overwhelmingly ‒ Inhalation of noxious substance ‒ Resp. infections in early childhood, AATD deficiency Pathophysiology of COPD Proposed model – toxin is inhaled • Oxidative stress induced • PMNs and macs recruited and activated • Oxidative burst occurs; proteolytic enzymes released; antiproteases inhibited • Inflammation enhanced, thickening basement membrane in bronchi and increasing mucus production • Tissue destroyed, including elastin • Excess proteases and loss of elastin results in damage to alveoli (air sacs) and collapse of airway during exhalation • End result – narrowing of airways and impaired air exchange from loss of alveoli https://thoracickey.com/wp-content/uploads/2017/01/image06960.jpeg