Respiratory Tract Disease 

Atelectasis	Obstructive Lung Disease
Restrictive Lung Disease	Pneumoconioses
Vascular Lung Disease	Infection
Tumors

Atelectasis (Collapse) 
     Inadequate airway expansion leads to ventilation-perfusion imbalance and
     ultimately hypoxia.  The two most common causes of atelectasis are
     compression and resorption.

Resorption Atelectasis
     When an airway becomes obstructed, alveolar gas trapped distal to the
     obstruction is absorbed and those areas collapse.  Obstruction may result from:
          1.   Foreign objects
          2.   Mucus plugs (postoperative hypoventilation)
          3.   Bronchial asthma
          4.   Cystic fibrosis
          5.   Chronic bronchitis
          6.   Tumors

Compressive Atelectasis
     Compressive lung collapse usually results from pleural accumulation of fluid,
     blood, or air.  Common causes include:
          1.   Left heart failure
          2.   Pheumothorax
          3.   Pleuritis


Obstructive and Restrictive Lung Disease 
     Obstructive lung disease causes an increase in airflow resistance due to either
     physical obstruction or loss of elastic recoil.  The impact of these types of
     disorders includes:
          1.   Normal Total Lung Capacity (TLC)
          2.   Normal Forced Vital Capacity (FVC)
          3.   Decreased Forced Expiratory Volume (FEV1.0)
     Restrictive lung disease results from interference of normal chest wall
     expansion and interstitial lung disease.  The impact of these types of disorders
     includes:
          1.   Decreased FVC
          2.   Normal FEV1.0

Obstructive Lung Disease
     Asthma
          This multifactorial disease is characterized by the presence of episodic,
          reversible bronchospasm triggered by exaggerated bronchoconstrictor
          response to various stimuli.  Incidence rate is 5% of adults and 7-10% of
          children.  Two major classifications are extrinsic and intrinsic disease.
     Extrinsic Asthma (Early Onset)
          This immune mediated form can result from exposure to allergens
          (atopic), occupational toxins, or infection (Aspergillus).  In all cases it
          appears to be mediated by a type I hypersensitivity reaction resulting in
          IgE dependent mast cell and basophil degranulation.  Release of histamine
          and other bronchial and vasoactive substances results in both reversible
          bronchoconstriction and ongoing airway inflammation.

     Pathogenesis
          1.   Exposure to allergen
          2.   Mast cell release of histamine
          3.   Mast cell release of IL-4, IL-5
          4.   IL-4, IL-5 stimulation of IgE and eosinophils
          5.   Mast cell release of leukotrienes (C4,D4,E4), prostaglandins (PGD2),
               and platelet activating factor (PAF) promote bronchoconstriction,
               mucus secretion and eosinophil recruitment.
          6.   Mast cell release of TNF-alpha promotes I-CAM expression by
               endothelial cells and ultimately epithelial NO depletion.
          7.   Eosinophil release of major basic protein (MBP) and eosinophil
               cationic protein (ECP) promote further epithelial injury.
          8.   Depletion of epithelial relaxing agents may increase sensitivity to
               further exposures to allergen.

     Pathology
               1.   Edema, hyperemia, inflammatory cell infiltration.
               2.   Increased mucus secretion
                         Curschmann's spirals: mucus plugs + eosinophils
                         Charcot-Leyden crystals: mucus plugs + eosinophil
                         protein
               3.   Patchy epithelial cell necrosis
               4.   Increased basment membrane collagen deposition
               5.   Mucus gland hypertrophy and hyperplasia
               6.   Smooth muscle cell hypertrophy and hyperplasia
     Clinical: Reversible severe dyspnea and wheezing
               Lung hyperinflation
               Bronchospasm lasts 1-several hrs.
               Status asthmaticus - often fatal

     Intrinsic Asthma (Adult Onset)
          Non allergic mediated airway hypersensitivity.  Exposure to:
               1.   Airway viral infections
               2.   Air pollution
               3.   Aspirin
               4.   Exercise

     Degree of bronchospasm is severe.  Defect may be increased sensitivity of
     airway receptors to noxious agents or autonomic abnormality.

Chronic Obstructive Pulmonary Disease
     Emphysema
          This disease is characterized by the development of interalveolar wall
          destruction with airspace enlargement.  The two most common forms of
          emphysema are centriacinar and panacinar disease.

     Centriacinar (Centrilobular) Emphysema
          This form of emphysema is seen primarily in smokers.  Destruction of the
          alveoli septa occurs in the proximal portions of the lung, sparring the more
          distal peripheral alveoli.

     Panacinar (Panlobular) Emphysema
          This form of emphysema is seen primarily in individuals with the genetic
          disease resulting in alpha1 anti-trypsin deficiency.  In this condition
          septal destruction is more uniform involving both proximal and distal
          portions of the terminal acinus.

Pathogenesis
     In either form of the disease, there is an imbalance in the ratio of
     protease/elastase production and available antiprotease activity.  In panacinar
     emphysema the patient lacks sufficient antiprotease to counteract even normal
     release of protease.  In smokers, elements in tobacco both promote protease
     release (cell injury) and inhibit the antiprotease system.

     Clinical:
          Progressive dyspnea
          Barrel chest
          Pink Puffer
          Blue Bloater
     Course:   Death occurs from - 
                    1.   Respiratory failure
                    2.   R. heart failure

Chronic Bronchitis

     Disease seen primarily in cigarette smokers and people exposed to high levels of
     air pollution.  Disease is defined as the development of a persistent productive
     cough for at least 3 consecutive months in at least 2 consecutive years.  It is
     estimated that 5-15% of cigarette smokers develop clinically significant COPD.
     Pathogenesis:  Toxin irritation
                         Mucus hypersecretion
                         Mucus gland hypertrophy
                         Mucus gland hyperplasia
                         Airway wall fibrosis
     Clinical:      Productive cough
                    Outflow obstruction
                    Emphysema

Bronchiectasis
     Permanent dilatation of bronchi/bronchioles resulting from obstruction or
     chronic infection.
     Clinical:      Purulent sputum
                    Hemoptysis


Restrictive Lung Disease 
     These diseases interfere with lung expansion.  Damage (acute or chronic) to
     alveolar epithelium or capillary endothelium (Interstitial disease) results in
     increased effort for ventilation, and abnormalities in the ventilation-perfusion
     ratio.  This may lead to hypoxia, pulmonary hypertension, respiratory failure,
     and cor pulmonale.

     Acute Restriction 
          Adult Respiratory Distress Syndrome (ARDS)
               This condition is the reaction to a number of pulmonary stresses.
                    1.   Sepsis
                    2.   Diffuse Pulmonary Infection (Viral)
                    3.   Gastric Aspiration
                    4.   Mechanical Trauma (Hypovolemia)
                    5.   Near Drowning
                    6.   Severe Burns
          Whether the damage to the alveolar interstitium begins with the alveolar
          epithelium or vascular endothelium, the consequences are similar.
               1.   Decreased arterial O2 pressure
               2.   Decreased lung compliance
               3.   Diffuse pulmonary infiltrate

          The development of the pulmonary infiltrate leads to the formation of a
          hyaline membrane composed of blood proteins and necrotic cells. 
          During the healing phase, fibrosis and pneumocyte proliferation may lead
          to permanent lung changes.
          Clinical:           Hypoxemia
                              Respiratory Distress
                              Secondary Infection
          Course:             Highly fatal in acute stage (50%)
                              Lung function restored in 4-6 months.

Chronic Restrictive Disease
     This is a large heterogeneous group of disorders with mostly unknown etiology. 
     The common link is that patients eventually develop reduced FVC with
     proportional reduction in FEV1.0.  Thus FEV1.0 / FVC ratio remains near normal
     unlike that seen in obstructive disorders.
     Some of the forms of chronic restrictive disease include: (* most common)
     *         1.   Environmental agents (Pneumoconioses)
     *         2.   Collagen vascular disorders
                    Scleroderma
                    SLE
                    Rheumatoid Arthritis
                    Dermatomyositis
     *         3.   Sarcoidosis
     *         4.   Idiopathic Pulmonary Fibrosis (IPF) Hamman-Rich syndrome
               5.   ARDS
               6.   Wegener's granulomatosis
               7.   Goodpasture's syndrome


     Idiopathic Pulmonary Fibrosis

          Alveolar wall injury leads to chronic inflammation of the interstitium
          (alveolitis).  Long term fibrosis leads to:

               1.   Hypoxemia
               2.   Cyanosis
               3.   Honeycomb Lung (End Stage Lung)
               4.   Respiratory Failure
               5.   Cor pulmonale

     Sarcoidosis

          Noncaseating granulomatous systemic disease with unknown etiology.
          Most patient remain asymptomatic or respond to therapy.  Those with
          severe lung involvement may develop restrictive disease with
          consequences similiar to above.


     Pneumoconioses 

          Group of disorders caused by inhalation of inorganic dusts, gases, vapors,
          and organic material.  The most important pathologic feature is stimulation
          of fibrosis.  The concept of individual susceptibility is important in the
          clinical manifestation of these diseases and represents differences in
          airway anatomy and function, clearance mechanisms and other defence
          mechanisms, and overall immunocompetency.

     Silicosis
          Fibrotic response to inhaled silica.
               1.   Occupational Hazard seen in sandblasting, mining, metal
                    working, ceramics, and foundry work.
               2.   Ingestion of silica crystals results in macrophage toxicity with
                    release of fibroblast stimulating factors.
               3.   Pattern of lung fibrosis is termed nodular fibrosis.
     Asbestosis
          Fibrotic pulmonary response to inhalation of asbestos.
     
               1.   Asbestos body 
               2.   Pattern of fibrosis is termed - diffuse fibrosis
               3.   Increased risk for bronchial cancer
               4.   Increased risk for mesothelioma


Pulmonary Vascular Disease 
     Pulmonary Thromboembolism
          Most common cause of preventable death in hospitalized patients
          (50,000/yr).  The primary (90%) site of origin in the deep veins of the
          lower extremities.  Risk factors include:
               1.   Prolonged bed rest (immobilization)
               2.   Lower extremity surgery
               3.   Severe trauma (multiple fractures, severe burns)
               4.   Congestive heart failure
               5.   Parturition/High Estrogen birth control pills

          The consequences of embolic blockage of pulmonary arteries is mainly
          dependent on size of the embolus and thus size of occluded artery.  The
          two primary consequences of embolic blockage are:
               1.   Pulmonary arterial hypertension
               2.   Ischemia of distal lung parenchyma

          Clinical:      Asymptomatic (60-80%)
                         Acute cor pulmonale and sudden death (5%) with > 60%
                         reduction in pulmonary flow
                         Limited zone of infarction (15%) with dyspnea
                         Recurrent emboli (3%) lead to chronic pulmonary
                         hypertension and cor pulmonale


Pulmonary Infection 
     Pneumonia is responsible for about 17% of all deaths in the U.S.  The two major
     forms of lung infection are bacterial pneumonia with alveolar consolidation and
     atypical pneumonitis (viral) with alveolar interstitial inflammation.

Acute Bacterial Pneumonia
     The primary characteristic of bacterial pneumonia is the development of intra-alveolar
     exudation leading to consolidation (solidification). The two main
          patterns of lung involvement are lobar pneumonia and bronchopneumonia. 
      Lobar pneumonia is the result of Streptococcus pneumoniae (pneumococcus)
          infection in 90% of the cases.
     Lobar Pneumonia
          This form of pneumonia is primarily seen in middle age patients.
               1.   Acute Congestion
               2.   Red Hepatization
               3.   Grey Hepatization
               4.   Resolution
     Bronchopneumonia
          Form of pneumonia primarily seen in the very young and elderly. 
          Consolidation occurs but its pattern is patchy distribution often in both
          lungs.
     Clinical:      Fever, dyspnea, cough
                    Purulent rust colored sputum
                    Chest pain
     Course:        Most cases are resolved
                    Bacteremia leading to meningitis and endocarditis
                    Abscess formation
                    Empyema
     Atypical (Viral/Mycoplasma) Pneumonia
          This form of pulmonary inflammation is seen in children and young adults. 
          It is characterized by the lack of alveolar exudation and consolidation. 
          The inflammation is restricted to the pulmonary interstitium.
          Clinical:      Highly variable
                         Fever, chest pain, malaise
                         Nonproductive cough

Lung Tumors 
     The lungs are frequent sites for both metastatic cancer and the development of
     primary tumors.  The majority of primary cancers of the lung are derived from
     the bronchial epithelium and thus termed bronchogenic carcinomas.

     Bronchogenic Carcinoma
          Number one cause of cancer related death in the U.S. (1996- 158,000
          deaths).  This disease is seen in patients age 40-70 with smokers having a
          10X increased risk. The four major types of lung cancer are:
          *  1.   Squamous cell carcinoma
          *  2.   Adenocarcinoma
          *  3.   Large Cell Undifferentiated
             4.   Small Cell (Oat Cell) Carcinoma
     *    Cancers are grouped under the heading of non-small cell lung carcinoma
          (NSCLC) for therapeutic approach.  The other category is small cell lung
          carcinoma (SCLC).

     
     The etiology of lung cancer is tied to both genetic background and toxin
     exposure.  Many of the lung tumors show mutations in genes coding for tumor
     suppressors (p53) and there is strong statistical data linking smoking to lung
     cancer development.  The evidence is stronger when subjects are exposed to
     cigarette smoke and other inhaled toxins (asbestos, arsenic, nickel, vinyl
     chloride, etc.).

     Squamous Cell Carcinoma
          1.   Strong association with smoking
          2.   Central growth
          3.   Desmosome and Keratin synthesis

     Adenocarcinoma
          1.   Major tumor seen in non-smokers
          2.   Peripheral growth
          3.   Mucin secretion

     Large Cell Carcinoma          
          1.   Highly undifferentiated tumor
          2.   Tumor seen in smokers and non-smokers
          3.   May show characteristics of both squamous and adenocarcinoma

     Small Cell Carcinoma
          1.   Strongly associated with smoking
          2.   Central growth
          3.   Paraneoplastic syndromes

     Clinical:      Cough               75%
                    Weight loss         40%
                    Chest pain          40%  
                    Dyspnea             20%
                    Hoarsness
                    Meningitis/hepatomegaly/bone pain
                    Superior Vena Caval Syndrome
                    Atelectasis
                    Paraneoplastic syndromes

     Course:        Overall 5 yr survival 10%
                    Untreated SCLC      20 wks
                    Treated SCLC        1 yr.
                    5 yr survival for NSCLC
                        Stage I        50%
                        Stage II       20%
                        Stage III      5%