PULMONARY PATHOLOGY V Acute Lung Injury

Nils Lambrecht, MD, PhDnilslam@uci.edu

Nils.Lambrecht2@va.gov

November 16th, 2015

READING ASSIGNMENT

Robbins Basic Pathology 9th Edition Pp. 460-462 – ARDS PP. 250-252 – Neonatal RDS

Pathoma 2015 Edition:

Pulmonary 5 – Acute Lung InjuryINTEGRATION REPORT

ANATOMY: Lungs (Wiki) 10/16/14 HISTO: Respiratory Podcast

1/12/15 PHYSIO: Blood Gases (Longmuir)

1/23/15 PHYSIO: Lung mechanics-

surfactant (Longmuir) 1/16/15

Objectives

1. Learn pulmonary anatomy and histology

2. Define atelectasisa. Resorption (obstructive) atelectasisb. Compression atelectasis

c. Contraction atelectasis

3. Define pulmonary edemaa. Hemodynamic pulmonary edema

b. Edema caused by microvascular injury

4. Define acute (non-vascular and non-infectious) lung injury

a. Acute respiratory distress syndrome (ARDS) and diffuse alveolar damage (DAD)b. Respiratory distress syndrome (RDS) of newbornc. Acute Interstitial Pneumonitis (Hamman–Rich syndrome)d. Diffuse alveolar hemorrhage syndromes

- Goodpasture syndrome- Idiopathic pulmonary hemosiderosis - Pulmonary angiitis (Wegners

granulomatosis)

SignificanceThe 10 leading causes of death

Lung Anatomy (I)

Lung Anatomy (II)

Lung Histology (I)

Lung Histology (II)

Atelectasis

Incomplete expansion (neonatal atelectasis)

or collapse of previously inflated lung, which is reversible.

Occurs when an obstruction prevents air from reaching distal airways:- Mucus- Aspiration- Tumor- Enlarged

peribronchial lymph nodes

Associated with accumulation of fluid, blood, or air within the pleural cavity, which mechanically collapsesthe adjacent lung.

Local or generalized fibrotic changes in the lung or pleura hamper expansion

Poll Everywhere: Question 1

Which of the following is true regarding compression atelectasis?1. The mediastinum shifts toward the affected lung.2. A pneumothorax may cause this type of atelectasis3. A mucus plug in the bronchus may cause this type

of atelectasis4. The typical histologic picture is edema fluid filling

the alveolar spaces5. Diffuse fibrosis of lung parenchyma is the most

common cause of this type of atelectasis

Pulmonary edema

Fluid accumulation in the air spaces of the lungs

Intra-alveolar hemorrhage

Red blood cell accumulation in the air spaces

of the lungs

Pulmonary edema/hemorrhage

4A

Pulmonary edema

Intra-alveolar hemorrhage

Hemosiderin-laden macrophages (heart failure cells)

HEMODYNAMIC EDEMA

EDEMA DUE TO MICROVASCULAR INJURY

Pulmonary edema

Hemodynamic edema

Increased pulmonary venous pressure (common) Left-sided heart failure Volume overload Pulmonary venous obstruction (mediastinal

tumor) Decreased oncotic pressure (less common)

Hypoalbuminemia due to: Malnutrition Liver disease (decreased protein synthesis) Nephrotic syndrome (increased protein loss) Protein losing enteropathy

Edema due to microvascular injury

Leakage of fluid and proteins into the interstitial space and alveoliPulmonary hydrostatic pressure is not elevated!

Due to: Infections Inhaled gases Liquid aspiration

Drugs & chemicals Shock, trauma Radiation Transfusion related

Question 2 Edema associated with left sided congestive

heart failure:1. is due to increased hydrostatic pressure in the

alveolar capillaries.2. causes hyaline membranes to form.3. is more pronounced in the upper lobes4. results in collapse of alveoli5. is a result of microvascular injury

Adult Respiratory Distress Syndrome (ARDS)

Clinical syndrome of acute onset of severe respiratory distress with cyanosis & hypoxemia

Refractory to O2 therapy X-ray Diffuse infiltrate Diffuse alveolar damage (DAD) is the histological

manifestation of ARDS Decreased lung compliance No evidence of left-sided cardiac failure

>50% cases of ARDS: Sepsis Diffuse pulmonary infections Gastric aspiration Mechanical trauma including head

injury

ARDS Etiology

Direct effects Systemic effects

Aspiration TraumaGastric contents SepsisHydrocarbons Acute pancreatitisSalt or fresh water Multiple transfusions

Pulmonary infections BurnsBacterial (gram positive and Cardiopulmonary bypass gram negative) Reperfusion after lung transplantFungal Granulocytic leukemiaMycobacterial Drug exposureViral HeroinMycoplasmal MethadonePneumocystic Acetylsalicyclic acid

Inhalation PlacidylNO2, Cl2, SO2, NH2, O2 Paraquat

Smoke DIC Fat embolism UremiaPulmonary contusion

ARDS Etiology

Imbalance of pro-inflammatory & anti-inflammatory mediators

Pulmonary macrophages increase IL-8, IL-1& TNF synthesis endothelial activation, sequestration and activation of neutrophils

NEUTROPHILS ARE THOUGHT TO HAVE AN IMPORTANT ROLE IN THE PATHOGENESIS OF ARDS

Activated neutrophils damage epithelium & endothelium vascular leakiness & loss of surfactant Fibrin secretion Hyaline membranes

Pathogenesis of ARDS

Clinical course of ARDS

Early or acute or exudative phase: First week (85% within 72 hrs), mortality is about 26-

58%

Late or proliferative phase: More than 1-2 weeks up to one year Death due to progressive fibrosis in 40% of patients

Sequelae: Decreased lung function due to interstitial fibrosis

(restrictive lung disease, 80% of patients) Cognitive, psychiatric abnormalities (30-50% of patients) Physical weakness (50-60% of patients)

Acute (exudative) phase

Profound dyspnea & tachypnea

Increasing cyanosis and hypoxemia

Diffuse bilateral infiltrates on X-Ray

Acute Congestive phase

Normal

Diffuse Alveolar Damage

Edema

Congestion

Hyeline membranes: fibrin rich edema fluid + remnants of necrotic epithelial cells

Late or proliferative phase

Resorption of exudate and removal of dead cells by macrophages

Release of TGFβ and PDGF and replacement by:

Fibrosis Epithelium

Proliferation of type II pneumocytes Bronchoalveolar stem cells

Endothelium Migration from adjacent capillaries Marrow-derived endothelial progenitor

cells

Interstitial fibrosis

Type II pneumocyte proliferation

Residual hyaline membranes

Organizing phase

Acute phase

Fibro-proliferation in ARDS

Advanced Interstitial Fibrosis

“Honeycomb Lung”

Advanced Interstitial Fibrosis

“Honeycomb Lung”

Neonatal Respiratory Distress Syndrome (NRDS)

Affects about 1% of newborn infants.

Is the leading cause of death in preterm infants.

Is histologically characterized by hyaline membranes covering the alveolar walls.

Preterm infant, appropriate for gestational age Usually male, delivered by cesarean section &

associated with maternal diabetes Require resuscitation at birth normal color

established within 30 minutes difficulty breathing and cyanosis

Chest X-ray ground-glass picture Difficult to treat If the baby survives for 3-4 days excellent chance of

recovery

NRDSPresentation

Incidence of NRDS is inversely proportional to gestational age(60% < 28 weeks; 30% between 28-34 weeks; <5% in >34 weeks

Surfactant production accelerated after 35th week gestation in fetus

High inspiratory pressures required at first breath 40% of residual air volume retained after first breath with

normal surfactant Surfactant deficiency collapse of lung after each breath

infant works equally hard with each breath Progressive collapse & reduced lung compliance

NRDSEtiology

Infants of diabetic mothers: maternal hyperglycemia → compensatory fetal

hyperinsulinemia → reduced surfactant synthesis

Infants born with cesarean section:

Labor increases surfactant synthesis

Conditions associated with intrauterine stress Increased surfactant synthesis lower risk of RDS

NRDSRisk factors

NRDSCause

Fundamental defect is deficiency of pulmonary

surfactant

complex mixture of phospholipids synthesized & secreted by type 2 alveolar cells.

present at the air-liquid interface of alveolar lining layer

NRDSPulmonary surfactant (I)

90% phospholipids & 10% proteins1) Phospholipids

Phosphatidyl choline principle component Phosphatidyl glycerol

2) Proteins SP-A, hydrophilic SP-B, hydrophobic SP-C, hydrophobic SP-D, hydrophilic

NRDSPulmonary surfactant (II)

Phosphatidyl choline & Phosphatidyl glycerol are absolute requirements for surfactant function

SP-B and SP-C are hydrophobic and may be needed to carry phosholipid molecules to air liquid interface Mutations of SP-B & SP-C genes severe

respiratory failure SP-A and SP-D are hydrophilic; bind

microbial surface antigens and act as opsonins

NRDSPulmonary surfactant (III)

NRDSPathophysiology

Maturity and birth weight Promptness of institution of therapy

NRDSPrognosis

NRDSDiagnosis and prevention

Diagnosis: Analysis of amniotic fluid phospholipids

good estimate of surfactant level in fetal lung

Prevention: Inducing maturation in fetus at risk Prophylactic administration of surfactant to

premature infants Antenatal corticosteroids administration After birth:

Surfactant replacement therapy Oxygen

NRDSComplications (I)

Retrolental fibroplasia (retina is incompletely vascularized due to oxygen therapy)

decrease in VEGF endothelial cell apoptosis retinal tissue ischemic retinal scarring scar tissue can pull the retina off the back of

eye retinal detachment visual impairment

NRDSComplications (II)

Bronchopulmonary dysplasia (BPD) due to oxygen therapy Hyperoxemia, hyperventilation, prematurity,

inflammatory cytokines & vascular mal-development Defined clinically as oxygen dependence to 28 days post-

natally Oxygen delivery under high pressures necrotizing

bronchiolitis and alveolar septal injury Recent years milder injury arrest of lung maturation in

the saccular stage of development (simplified acini)

Question 3

All of the following are true about hyaline membrane disease of the newborn is true EXCEPT:1. It is most common in neonates less than 32 weeks

gestational age2. It can be prevented by administration of corticosteroids to

the mother during gestation3. It is characterized microscopically by dense eosinophilic

proteinaceous material along the inner walls of the alveolar spaces

4. It is due to increased surfactant production by the lung5. Oxygen therapy for hyaline membrane disease of the

newborn may lead to bronchopulmonary dysplasia

Acute Interstitial Pneumonitisor Hamman–Rich syndrome

ARDS with interstitial lung disease in previously healthy patients

Older than 40 years of age, no sex predilection Unknown cause, rapid progression to acute

respiratory failure. Mortality of 33% to 74%

Most deaths occur within 1-2 months Substantial fraction of patients develop recurrent ALI

Diffuse alveolar hemorrhageGoodpasture syndrome

Proliferative, usually rapidly progressive glomerulonephritis with acute hemorrhagic interstitial pneumonitis

Antibodies against α3 chain of collagen IV Diffuse alveolar hemorrhage with focal necrosis of

alveolar walls, intra-alveolar hemorrhages, fibrous thickening of the septa, and type II pneumocyte hyperplasia.

Linear pattern of immunoglobulin deposition (usually IgG, sometimes IgA) in alveolar walls

Iron stain

Robbins and Cotran Pathologic Basis of Disease, 9th ed.

Diffuse intra-alveolar hemorrhage with hemosiderin-laden macrophages

Diffuse alveolar hemorrhageIdiopathic pulmonary

hemosiderosis

Rare disease of immune-mediated but unknown etiology that has pulmonary manifestations and histologic features similar to Goodpasture syndrome but without renal manifestation or circulating antibodies

Diffuse alveolar hemorrhagePulmonary angiitis

(Wegener Granulomatosis)

Bilateral acute pneumonitis with nodules and cavitary lesions

Combination of small vessel necrotizing vasculitis (angiitis) and necrotizing granulomatous inflammation

PR3-ANCAs are present in close to 95% of cases chronic sinusitis (90%), mucosal ulcerations of the

nasopharynx (75%), and renal disease (80%)

Wegener granulomatosis

Vasculitis of a small artery with adjacent granulomatous inflammation including giant cells

large nodular cavitating lesions

Robbins and Cotran Pathologic Basis of Disease, 9th ed.