Subject: Phathology Topic: DISEASES OF THE RESPIRATORY TRACT- 1 Lecturer: Dra.

Dela Fuente Date of Lecture: October 2011 Transcriptionist: The Soloist Pages: 14

Respiratory function: Ventilation- entry of air Perfusion- blood in capillaries Respiratory gas exchange

Anatomy: The lungs is divided into segments or lobules or lobes, the right lung is divided into 3 lobes while the left lung is divided into 2 lobes

Acinus- main respiratory unit; where gas exchange occurs Anteriorly: mostly upper lobe Posteriorly: mostly lower lobes; upper parts of the lower lobe are quite thin and are located laterally. Starts with the respiratory bronchiole alveolar duct alveolar sacs Before the respiratory bronchiole we have the terminal bronchiole Group of 3 acini = lobule As you go down distally smooth muscles also disappears. Cross-section of the acinus

Trachea- contains C-shaped cartilage rings but as you go down distally these rings will be replaced by cartilage plates and will eventually disappear as you go more distally along the airway.

Pores of Kohn- holes in between alveolar spaces that facilitate

11

SY 2011-2012

movement of air from one alveolar sac to another and not only air but also exudates in cases of infections which promotes spread of infection from one alveolar space to another.

In some disease states, these glands undergo hyperplasia and hypertrophy inc. mucus secretion (seen in chronic bronchitis) Smooth muscles can also undergo hypertrophy which is seen in Bronchial asthma

On a closer view: alveolar structure that is lined by pneumocytes and also characterized by the presence of macrophages. Alveolar capillaries- are closely apposed to the alveolar epithelium that they share a common basement membrane which helps in the efficient diffusion of gases between the capillaries and the alveolar spaces. Above: here the walls become thinner (to facilitate easier diffusion of gases) as you go down. Terminal bronchioleresp. bronchiole alveolar duct alveolar sac In some disease states the thin wall of the alveoli may become thickened and this would lead to inefficient diffusion of gases. Familiarize yourself with this diagram for it will be the basis of lung pathologies

Lining: Ciliated Pseudostratified columnar epithelium with goblet cells. The cilia are responsible for the mucociliary movement. As you go down the ciliated epithelium is replaced by the mucus-secreting epithelium.

In between the epithelium and the cartilage, we have the bronchial glands or mucus glands and we also have smooth muscles.

Alveolar space- lined by 2 types of pneumocytes (alveolar epithelium). Types 1 and 2.

11

Though type 1 comprises 90% of the lining epithelium Type 2 is more plentiful than type 1. Type 1 pneumocytes are membranous, flattened/plate-like. Type 2 are round in shape Type II cells are important for at least two reasons: (1) They are the source of pulmonary surfactant, contained in osmiophilic lamellar bodies seen with electron microscopy, and (2) they are the main cell type involved in the repair of alveolar epithelium after destruction of type I cells. But the problem with this is that type 2 cells are not membranous, they are thick. Such that their proliferation impairs gas exchange. The surfactant reduces the surface tension throughout the lungs, contributing to its compliance which in turn prevents it from collapsing. Within the alveolar space are the alveolar macrophages which are the last line of defense in the pulmonary defense mechanism. These cells are phagocytic and are capable of secreting mediators which can cause changes in the alveolar epithelium. Interstitium- In between alveolar spaces which is composed of interstitial cells. When the lungs is injured, these cells proliferate and causes the interstitium to become fibrotic. Pulmonary capillaries are also located in the interstitium through w/c blood will pass. Shares a common basement membrane with the alveolar space. Factors involved in the maintenance of adequate respiration: 1. Adequate air intake 2. Rapid diffusion along alveolar ducts and thru alveolar walls (approx 10 ms) 3. Adequate blood flow or perfusionpulmonary capillaries Inadequate air supply to the alveoli (hypoventilation)

1. CNS lesions affecting respiratory ctrs 2. Paralysis of muscles of respiration (diaphragm and intercostals) 3. Injuries/deformities of thoracic skeleton 4. Pleural effusion or pneumothorax 5. Bronchial obstruction (tumor, foreign body, mucus, narrowing of walls due to bronchoconstriction, fibrosis)- can be intraluminal or extraluminal (tumors) Impaired diffusion of gas 1. Reduction in total alveolar surface area No of alveoli- 700 million Surface area- 1 tennis court or 70 sq. meters 2. Increase in distance over which diffusion takes place Alveolar diameter- approx. 20 micrometer Increasing the diameter will slow down gas diffusion/ gas exchange

3. Increase in thickness of alveolar capillary membrane- fibrosis Altered pulmonary perfusion- enough ventilation but not enough blood perfusion 1. Occlusion of large vessels by multiple emboli Usual source of emboli: deep leg veins 2. Slowing of pulmonary circulation 3. Reduction in pulmonary capillary bed (in diffuse lung disease)

11

4. Pulmonary vascular spasm due to hypoxia In systemic circulation when you have hypoxia, blood vessels will tend dilate to compensate but in the lungs hypoxia induces vasoconstriction in order to shunt the blood in well ventilated areas. Ventilation-Perfusion Mismatch Dead air space areas of the lung that are ventilated but not perfused (not enough blood flow) Shunt areas of the lungs that are perfused but not ventilated

Lung buds arises from the foregut

Pulmonary Hypoplasia Defective development if both lungs resulting in decreased weight, volume and acini Can be bilateral or unilateral Normal lung: crepitant

Pulmonary Defense Mechanisms Nasal clearance (>10 m) LARGER particles Tracheobronchial clearance (2-10 m) coughed-out by mucociliary apparatus Alveolar macrophages (<2 m)

Bronchogenic Cyst - abnormal detachment of a fragment of the primitive gut Lined by ciliated columnar epithelium

-contains: mucus glands, smooth muscle, elastic tissue and cartilage Since there is abundant mucus glands which produces mucus, this condition then becomes favorable nest for infection. It also has the tendency to rupture when it becomes so large.

11

more often associated with other anomalies with separate blood supply

Intralobar within the visceral pleura within visceral pleura surrounded by normal lung venous drainage via pulmonary veins (95%) not often associated with other congenital anomalies may be an acquired postinflammatory process

Pulmonary Sequestration non-functioning lung tissue separate from normal bronchopulmonary tree separate blood supply 2 types: Extralobar and intralobar

Extralobar outside the visceral pleura outside normal lung pleura venous drainage via systemic veins (75%) 11 Clinical significance of congenital cysts:

Compression or displacement of significant lung volume Development of infection Progressive cystic dilatation Rupture

ATELECTASIS- collapsed of lung parenchyma- becomes liver-like -refers either to incomplete expansion of the lungs (neonatal atelectasis) or to the collapse of previously inflated lung, producing areas of relatively airless pulmonary parenchyma. Acquired atelectasis, encountered principally in adults, may be divided into resorption (or obstruction), compression, and contraction atelectasis Obstructive- Resorption atelectasis is the consequence of complete obstruction of an airway, which in time leads to resorption of the oxygen trapped in the dependent alveoli, without impairment of blood flow through the affected alveolar walls. Since lung volume is diminished, the mediastinum shifts toward the atelectatic lung. Resorption atelectasis is caused principally by excessive secretions (e.g., mucous plugs) or exudates within smaller bronchi and is therefore most often found in bronchial asthma, chronic bronchitis, bronchiectasis, and postoperative states and with aspiration of foreign bodies. NOTE: Although bronchial neoplasms can cause atelectasis, in most instances they cause subtotal obstruction and produce localized emphysema. Compressive- results whenever the pleural cavity is partially or completely filled by fluid exudate, tumor, blood, or air (the lastmentioned constituting pneumothorax) or, with tension pneumothorax, when air pressure impinges on and threatens the function of the lung and mediastinum, especially the major

vessels. Compression atelectasis is most commonly encountered in patients with cardiac failure who develop pleural fluid and in patients with neoplastic effusions within the pleural cavities. Similarly, abnormal elevation of the diaphragm, such as that which follows peritonitis or subdiaphragmatic abscesses or occurs in seriously ill postoperative patients, induces basal atelectasis. With compressive atelectasis, the mediastinum shifts away from the affected lung Contraction- fibrotic changes (localized or generalized) in the lung and pelura which prevents full expansion

NOTE: Significant atelectasis reduces oxygenation and predisposes to infection. Because the collapsed lung parenchyma can be re-expanded, atelectasis is a reversible disorder (except that caused by contraction).

Morphology: Collapsed lung parenchyma Red-blue, rubbery, subcrepitant ( no air inside) Slit-like alveoli (instead of wide open)

11

Right lung: Atelectatic Left: Normal Compressive Atelectasis- mediastinal stucture are pushed toward the nonatelectatic lung

>> The arrow to the left points the nonatelectatic alveoli while the one on the lower right points the atelectatic alveoli (slit-like alveoli)

Case: stab wound on the right side of the chest will result to compressive atelectasis due to hemothorax and pneumothorax pushing mediastinal structure towards the non atelectatic lung. PULMONARY EDEMA

*Closer view of the slit like alveoli*alveolar membrane are close to each other Obstructive Atelectasis- towards atelectatic side Outward forces: Vascular hydrostatic pressure & tissue oncotic pressure (at a lesser degree) - causing edema Inward forces: Intravascular oncotic pressure and Tissue hydrostatic pressure Albumin- plasma proteins (responsible for plasma oncotic pressure)

11

Pulmonary Edema: Mechanisms 1. Hemodynamic disturbance a. Increased venous & capillary pressure (hydrostatic pressure)- seen in left-sided heart failure, mitral valve stenosis, volume overload and pulmonary vein obstruction b. Decreased oncotic pressurehypoalbuminemia- liver failure, malnutrition, nephrotic syndromealbumin is excreted in the urine; seen also in protein-losing enteropathy c. Lymphatic obstruction 2. Microvascular injury - increased capillary permeability (Bacterial, viral, mycoplasma and ricketssial) The last 3 causes damage to the pulmonary capillaries
Causes: Lifted from Robbins Infections: pneumonia, septicemia Inhaled gases: oxygen, smoke Liquid aspiration: gastric contents, near-drowning Drugs and chemicals: chemotherapeutic agents (bleomycin), other medications (amphotericin B), heroin, kerosene, paraquat Shock, trauma Radiation

>>Edema fluid (pink amorphous) w/in the alveoli The most common hemodynamic mechanism of pulmonary edema is that attributable to increased hydrostatic pressure, as occurs in left-sided congestive heart failure. Whatever the clinical setting, pulmonary congestion and edema are characterized by heavy, wet lungs. Fluid accumulates initially in the basal regions of the lower lobes because hydrostatic pressure is greater in these sites (dependent edema). Histologically, the alveolar capillaries are engorged, and an intra-alveolar granular pink precipitate is seen. Alveolar microhemorrhages and hemosiderinladen macrophages ("heart failure" cells) may be present. In long-standing cases of pulmonary congestion, such as those seen in mitral stenosis, hemosiderin-laden macrophages are abundant, and fibrosis and thickening of the alveolar walls cause the soggy lungs to become firm and brown (brown induration). These changes not only impair normal respiratory function, but also predispose to infection. The second mechanism leading to pulmonary edema is injury to the capillaries of the alveolar septa. Here the pulmonary capillary hydrostatic pressure is usually not elevated, and hemodynamic factors play a secondary 11

Transfusion related

3. Undetermined origin a. High altitude- w/o acclimatization, oxygen in air is less and causes hypoxia vasoconstriction which then causes hypertension (inc. pulmonary and endothelial damage. Occur at 8000 ft. High but may occur at 400o ft in susceptible individuals Dexamethasone- facilitates resorption of edema fluid b. Neurogenic (CNS trauma) seen in subarachnoid hemorrhage which increases intracranial pressure.

role. The edema results from primary injury to the vascular endothelium or damage to alveolar epithelial cells (with secondary microvascular injury). This results in leakage of fluids and proteins first into the interstitial space and, in more severe cases, into the alveoli. When the edema remains localized, as it does in most forms of pneumonia, it is overshadowed by the manifestations of infection. When diffuse, however, alveolar edema is an important contributor to a serious and often fatal condition, acute respiratory distress syndrome. ACUTE LUNG INJURY: Abrupt onset of significant hypoxemia & diffuse pulmonary infiltrates in the absence of cardiac failure (Non-cardiogenic pulmonary edema) Acute Interstitial Pneumonia idiopathic origin; widespread ALI/ARDS Acute Respiratory Distress Syndrome -Rapid onset of severe lifethreatening respiratory insufficiency, tachycardia, cyanosis and severe arteriolar hypoxemia that is refractory to oxygen therapy A.K.A. Shock lung, Traumatic wet lung Acute alveolar injury and Diffuse alveolar injury -Diffuse alveolar capillary & epithelial damage -Severe respiratory insufficiency -Profound hypoxemia -Refractory to oxygen therapy -Decreased lung compliance -Bilateral pulmonary infiltrates NOTE: More than 50% of cases are associated with: o o sepsis diffuse pulmonary infectionsviral, mycoplasma and pneumocystis pneumonia, military TB

o o

gastric aspiration mechanical trauma (head injury)

CAUSES: Direct Lung Injury pneumonia aspiration inhalation injury near drowning pulmonary contusion fat embolism Indirect Lung Injury sepsis severe trauma acute pancreatitis cardiopulmonary bypass massive transfusion drug overdose

ARDS pathogenesis: main player: cytokines increased synthesis of IL-8; release of similar compounds endothelial activation; pulmonary microvascular sequestration & activation of neutrophils (IL-1 & TNF) activated neutrophils release mediators that damage the alveolar epithelium & promote more inflammation IL-8 potent neutrophil chemotactic agent/activating agent NOTE: Normally neutrophils can be found in the lungs but in ARDS there is an increase in number of activated neutrophils which promoted endothelial damage.

Endothelial/epithelial injury o o increased vascular permeability leakage of protein-rich fluid into the interstitium exudation of fluid into alveolar spaces

11

deposition of plasma proteins, fibrin & cell debris in the injured alveolar walls hyaline membrane ARDS PATHOGENESIS:

Diffuse damage to alveolar capillary walls leakage of protein-rich fluid into the interstitium End result: INTERSTITIAL & ALVEOLAR EDEMA

space

Damage to pneumocytes type I exudation of fluid into alveolar Morphology: 1. Acute stage (1st wk after pulmonary injury) - heavy, red & boggy lungs - hyaline membrane 2. Resolution - organization of fibrin exudate fibrosis

deposition of plasma proteins, fibrin & epithelial debris on alveolar walls HYALINE MEMBRANE Disruption of surfactant airspace collapse Ventilation perfusion mismatch Stiffening of the lungs with decreased compliance (due to fibroblast proliferation)

ARDS: Main events & outcome:

>>Above: ARDS Interstitial edema

11

4. Underlying disorders- cardiac disease or cancer NOTE: The pathophysiologic response and clinical significance of pulmonary embolism depend on the extent to which the pulmonary artery blood flow is obstructed, the size of the occluded vessel(s), the number of emboli, the overall status of the cardiovascular system, and the release of vasoactive factors such as thromboxane A2 from platelets that accumulate at the site of thrombus. Emboli result in two main pathophysiologic consequences: respiratory compromise owing to the nonperfused, although ventilated, segment and hemodynamic compromise owing to increased resistance to pulmonary blood flow engendered by the embolic obstruction. The latter leads to pulmonary hypertension and can cause acute rightsided heart failure. MORPHOLOGY: Large emboli may impact in the main pulmonary artery or its major branches or lodge at the bifurcation as a saddle embolus. Sudden death often ensues, owing largely to the blockage of blood flow through the lungs. Death may also be caused by acute failure of the right side of the heart (acute cor pulmonale). Smaller emboli can travel out into the more peripheral vessels, where they may cause infarction. In patients with adequate cardiovascular function, the bronchial arterial supply can often sustain the lung parenchyma despite obstruction to the pulmonary arterial system. Under these circumstances, hemorrhages may occur, but there is no infarction of the underlying lung parenchyma. Only about 10% of emboli actually cause infarction. Although the underlying pulmonary architecture may be obscured by the suffusion of blood, hemorrhages are distinguished by the preservation of the pulmonary alveolar architecture; in such cases, resorption of the blood permits reconstitution of the preexisting architecture. Saddle Embolus

Above: Thickened alveolar walls due to inflammation and edema

>> Take note the presence of hyaline membrane on the alveolar walls (Pink amorphous material lining the walls) with a lot of inflammatory infiltrates in the intersitium. Diseases of Vascular Origin Pulmonary Embolism & Infarction Pulmonary Hypertension Diffuse Pulmonary Hemorrhage Syndromes

PULMONARY EMBOLISM: Risk Factors 1. Prolonged immobilization- hip fracture 2. Hypercoagulable states- either primary (e.g., factor V Leiden, prothrombin 20210 A, hyperhomocysteinemia, and antiphospholipid syndrome) or secondary (e.g., obesity, recent surgery, cancer, oral contraceptive use, pregnancy) 3. Indwelling central venous linesright atrial thrombus

11

ischemic necrosis of the lung substance within the area of hemorrhage, affecting the alveolar walls, bronchioles, and vessels. If the infarct is caused by an infected embolus, it is modified by a more intense neutrophilic exudation and more intense inflammatory reaction. Such lesions are referred to as septic infarcts, and some convert to abscesses.

Above: a big emboli in the pulmonary artery (can be unilateral or bilateral)lethal; immediate death Small emboli- lodge in smaller branches and patients may survive. Patients may either have infarction or no infarction because the lungs has a dual blood supply (Pulmonary artery and Bronchial artery- arises from the aorta). Usually, however, in individuals with a normal cardiovascular system small emboli induce only transient chest pain and cough or possibly pulmonary hemorrhages without infarction. Only in the predisposed, in whom the bronchial circulation itself is inadequate, do small emboli cause small infarcts In cases of small emboli in the branches of pulmonary artery, the branches from the bronchial artery can still supply this area. These emboli can cause a transient occlusion but reperfusion can cause hemorrhage. In cases of the elderly and patients with atherosclerosis (aorta), the blood supply coming from the bronchial artery may not be sufficient to re-supply the areas that are affected and you may have an infarction. Pulmonary infarct is hemorrhagic because it has dual blood supply and it has a very loose parenchyma and not compact. Appears as a raised, red-blue area in the early stages. Often, the apposed pleural surface is covered by a fibrinous exudate. The red cells begin to lyse within 48 hours, and the infarct becomes paler and eventually red-brown as hemosiderin is produced. With the passage of time, fibrous replacement begins at the margins as a gray-white peripheral zone and eventually converts the infarct into a contracted scar. Histologically, the diagnostic feature of acute pulmonary infarction is the

ABOVE: SEVERE PULMONARY HEMORRHAGE

ABOVE: EMBOLI IN PULMONARY ARTERY Clinical features depend on:

11

1. Extent of blood flow obstruction Saddle embolus= DEATH 2. Size of occluded vessel 3. Number & size of emboli 4. Cardiovascular status of patient 5. Vasoactive factors released by platelets MOST COMMON SOURCES OF LUNG EMBOLI (deep leg veins) External iliac v. Femoral v. Right side of heart Gonadal v. (ovarian & testicular) Uterine v. Pelvic venous plexus Lateral circumflex Femoral v. Soleal plexus Great saphenous v. Small saphenous v. LEAST COMMON SOURCES OF LUNG EMBOLI

1. Resolution 2. Pulmonary HPN 3. Development of second emboli 4. Death

PULMONARY HYPERTENSION Ppa = QR + Pla Ppa = pulmonary arterial pressure Increased is seen in Pulmonary congestion Q R Pla = pulmonary blood flow = pulmonary vascular resistance = left atrial pressure

INCREASE: Flow: in L R shunts (ASD &VSD) due to increased pressure in the left side of the heart Resistance: vasoconstriction capillary destruction (seen in extensive lung disease) postcapillary mitral stenosis LV

Deep femoral v. Popliteal v. Post. Tibial v.

Left atrial pressure: failure

Physiologic Effects Respiratory compromise Affected area is ventilated but not perfused Hemodynamic compromise Multiple emboli--- d resistance to pulmonary blood flow pulmonary HPN Consequences 11

CLASSIFICATION (WHO Venice 2003 Revised Classification System)

WHO Group I - Pulmonary arterial hypertension (PAH) Idiopathic (IPAH) Familial (FPAH) Asso.(APAH): collagen vascular disease congenital shunts between the systemic & pulmonary circulation, portal hypertension, HIV infection, drugs, toxins, or other diseases or disorders 1. Associated with venous or capillary disease WHO Group II - Pulmonary hypertension associated with left heart disease Atrial or ventricular disease Valvular disease (e.g. mitral stenosis)

Endothelial dysfunction Organization & incorporation of small emboli Neurohormonal vascular reactivity - chronic vasoconstriction Ingestion of substances which may injure the endothelium Morphology

Pulmonary HPN:

Recanalized or organized thrombus Medial hypertrophy Intimal & adventitial fibrosis Reduplication of elastic membranes Plexogenic pulmonary arteriopathy

WHO Group III - Pulmonary hypertension asso. with lung diseases and/or hypoxemia COPD, (ILD) Sleep-disordered breathing, alveolar hypoventilation Chronic exposure to high altitude Developmental lung abnormalities Small arteries and arterioles are usually affected Pulmonary HPN: Grades Grade I: medial hypertrophy Grade II: + intimal proliferation Grade III: intimal fibrosis; +/- occlusive Grade IV: plexiform lesions Grade V: rupture of pulmonary arteries Grade VI: fibrinoid necrosis HISTO: PULMONARY HPN

WHO Group IV - Pulmonary hypertension due to chronic thrombotic and/or embolic disease Pulmonary embolism in the proximal or distal pulmonary arteries Embolization of other matter, such as tumor cells or parasites

WHO Group V - Miscellaneous Pulmonary HPN: Mechanisms BMPR2 (bone morphogenetic protein receptor type 2)

11

Hi nga pala sa mga Groupmates ko sa anatomy lab, Tel, max, al, karla and Iami. Miss ko na mga gaguhan sessions ntn lalo na mga green jokes n Iami! Pizza party daw ulit tau sabi ni Iami sya sagot sa lahat ng gastos..di ba iami??

ABOVE: Medial hypertrophy

ABOVE: Plexogenic Pulmonary Arteriopathy So called because a tuft of capillary formations is present, producing a network, or web, that spans the lumens of dilated thin-walled, small, arteries

__________END OF TRANSCRIPTION__________ Batch 2014, Kindly read your books for a more detailed discussion of each of the topics. Ive already added some information from Robbins. Hopefully you guys will enjoy studying respiratory module as much as I did.

11