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Introduction to Respiratory Physiology Robert Padera, M.D., Ph.D. HBTM 235 September 19, 2014
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Goals To teach you everything something about respiratory physiology and pathology To set the stage for lecture on lung transplantation
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Outline Respiratory physiology – Lung anatomy – Mechanics of respiration – Control of respiration – Gas exchange – Pulmonary function tests Respiratory pathology – Emphysema – Usual interstitial pneumonia
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Respiratory System Central nervous system (medulla) Peripheral nervous system (phrenic nerve) Skeletal muscle (diaphragm, intercostals) Chest wall (ribs) Lung Conducting region (airways) Respiratory region (alveoli) Pulmonary vasculature Heart
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Anatomy Overview
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Lead inspired air to gas exchanging regions of the lung Components –Trachea –Mainstem bronchi –Lobar bronchi –Terminal bronchi (smallest airways without alveoli) Conducting Zone
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Respiratory Zone Gas exchanging region Surface area and volume Functional unit: acinus or lobule Components –Respiratory bronchioles –Alveolar ducts –Alveoli
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Alveolar Walls Diffusion Surface area Thin Elastin – contributes to recoil for expiration
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Lung Anatomy Vasculature
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Outline Respiratory physiology – Lung anatomy – Mechanics of respiration – Control of respiration – Gas exchange – Pulmonary function tests Respiratory pathology – Emphysema – Usual interstitial pneumonia
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Mechanics of Breathing Changing the shape, volume of thorax
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Inspiration Active process Contraction of diaphragm causes increase in intrathoracic volume and decrease in intrapleural, alveolar pressure Air rushes in, lung expands, energy stored in elastic fibers in alveoli and pleura, chest wall
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Expiration Passive process during quiet breathing –Diaphragm relaxes –Elastic recoil of lung, chest wall structures –Raises intrapleural, alveolar pressure –Air expelled Can add active component during exertion –Abdominal muscles –Internal intercostals
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Outline Respiratory physiology – Lung anatomy – Mechanics of respiration – Control of respiration – Gas exchange – Pulmonary function tests Respiratory pathology – Emphysema – Usual interstitial pneumonia
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Control of Respiration
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Outline Respiratory physiology – Lung anatomy – Mechanics of respiration – Control of respiration – Gas exchange – Pulmonary function tests Respiratory pathology – Emphysema – Usual interstitial pneumonia
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Gas Exchange Alveoli Diffusion down concentration gradient – O 2 highest in alveolus (airspace) – CO 2 highest in blood
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Outline Respiratory physiology – Lung anatomy – Mechanics of respiration – Control of respiration – Gas exchange – Pulmonary function tests Respiratory pathology – Emphysema – Usual interstitial pneumonia
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Pulmonary Function Tests: Spirometry
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Lung Volumes
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Pulmonary Function Tests: Diffusion Capacity (D L CO) Total gas exchange measurement Can be affected by many pathologies
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Outline Respiratory physiology – Lung anatomy – Mechanics of respiration – Control of respiration – Gas exchange – Pulmonary function tests Respiratory pathology – Emphysema – Usual interstitial pneumonia
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Pulmonary Pathologies Asthma (airways, inflammatory) Diffuse alveolar damage (alveoli) Pneumonia (infection, inflammatory) Lung cancer (malignancy) [Chronic obstructive pulmonary disease] [Usual interstitial pneumonia]
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Chronic Obstructive Pulmonary Disease (COPD) Diseases that cause airflow obstruction primarily during expiration Patients with COPD often show overlapping features of these specific disease entities: Emphysema Chronic bronchitis Bronchiectasis Asthma Small airways disease Reduced FEV 1
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Forced Expiration - Spirometry In obstructive lung disease (e.g., emphysema), both FVC and FEV 1 will be decreased, FEV 1 more so than FVC Monitor patients over time and effect of therapy
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Emphysema Abnormal permanent enlargement of the airspaces distal to the terminal bronchiole, accompanied by tissue loss via destruction of alveolar walls Often co-exists with chronic bronchitis Most strongly associated with cigarette smoking; most people develop symptoms after about 1-2 packs per day for 20 years Also associated with IV drug use, immune deficiency syndromes, vasculitis, connective tissue disorders
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NormalEmphysema
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NormalEmphysema
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NormalEmphysema Same magnification
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NormalEmphysema Same magnification
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Airflow Obstruction - 1 Due to collapse of small airways during expiration Damage to alveolar parenchyma leads to loss of elastic recoil of the lung, so it doesn’t provide as much “push” to expel the air The chest wall, diaphragm and abdominal muscles therefore need to squeeze harder to expel air; in addition, they are now pushing on a softer, floppier lung
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Airflow Obstruction - 2 Due to collapse of small airways during expiration Normal alveolar parenchyma is radially attached to small airways and tethers them open during expiration Loss of alveolar parenchyma in emphysematous lungs fails to adequately tether these small airways open, resulting in premature collapse during expiration
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“Experiment of Nature” Alpha-1 Antitrypsin (AAT) Deficiency AAT inhibits many proteases, including neutrophil elastase Production of AAT is increased during acute inflammation Patients with deficiency of AAT develop severe, early onset (40s- 50s) emphysema, even in the absence of smoking Patients with deficiency of AAT who smoke develop emphysema and destruction in their 20s-30s In animal models, emphysema is caused by: - Intratracheal administration of elastase - Recurrent pulmonary neutrophilia (source of elastase) - Genetic defects of native elastin (easier to degrade) Smoking increases acute inflammation in the lung, and leads to increased production of neutrophil elastases
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Emphysema: Pathogenesis
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Emphysema Pathogenesis Destruction of lung parenchyma Natural protective mechanisms Balance between destructive and protective mechanisms
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COPD – Inflammation Barnes et al, Clin Chest Med 2014; 35:71-86
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COPD – Oxidative Stress Barnes et al, Clin Chest Med 2014; 35:71-86
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COPD – Systemic Effects Barnes et al, Clin Chest Med 2014; 35:71-86
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Ross and Hansel, Clin Chest Med 2014; 35:219-39 COPD – Potential Therapies
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Outline Respiratory physiology – Lung anatomy – Mechanics of respiration – Control of respiration – Gas exchange – Pulmonary function tests Respiratory pathology – Emphysema – Usual interstitial pneumonia
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Usual Interstitial Pneumonia Also known as idiopathic pulmonary fibrosis UIP adds cells and fibrous tissue (scar) to the lung, thickening and stiffening it and restricting the elastic stretching, making inspiration harder Manifestations include: Decreased compliance – stiff lung Decreased lung volumes – spirometry measurements Impaired diffusion - D L CO measurement Abnormal small airway function Pulmonary hypertension
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Forced Expiration - Spirometry In a patient with a restrictive lung disease such as usual interstitial pneumonitis – primarily restricts inspiration - both the FVC and FEV 1 will be decreased, with a normal or even elevated ratio Monitor patients over time and effect of therapy
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UIP - Gross Honeycombing, most severe/earliest in lower zones, subpleural areas
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Pleural surface Heterogeneity UIP - Gross
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Temporal and spatial heterogeneity - patchy – End-stage (“honeycomb”) lung – Fibroblastic foci – Normal lung – Minimal active inflammation (usually) Architectural distortion - fibrosis UIP - Microscopic
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End-stage lungNormal lung Fibroblastic foci UIP - Microscopic
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End Stage (“Honeycomb”) Lung
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Fibroblastic Foci
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Normal Lung
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Clinics in Chest Disease – Table of Contents Pathogenesis of UIP
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Some form of injury to alveolar epithelium, either inhaled or blood-borne agents Acute and then chronic inflammation (as response to injury) of the alveolar interstitium, and alveolar exudate Persistence of injury (or repetitive injuries) leads to maintenance of chronic inflammation and eventual fibrosis Specific interstitial lung diseases will have different inciting injuries (many of which are still unknown) and different degrees/patterns of inflammation and fibrosis Both environmental and genetic factors likely play roles in determining if/when/how severe/what type of lung disease a patient will develop
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Pathogenesis of UIP
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UIP - Morphologic Progression Normal lung Fibroblastic foci End-stage lung
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Ahluwalia et al. Am J Respir Crit Care Med; 2014 Aug 4 (epub) UIP – Proposed Therapies
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Summary and Foreshadowing Respiration requires coordinated effort of central and peripheral nervous system, the skeleton and skeletal muscle, lungs and heart COPD and UIP are pulmonary diseases that can progress to respiratory failure requiring lung transplantation (Mon. 9/22) What might be challenges to the use of stem cells for repair or regeneration of the lung, given the gross and microscopic pathologies of COPD and UIP?
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