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Lung Development

• The respiratory system develops from the ventral wall of the foregut during embryogenesis
• The developing midline trachea branches into lung buds.
• The right lung bud splits into three main bronchi, while the left splits into two, resulting in three lobes on the right and two on the left.
• Continuing bifurcation of the main bronchi leads to smaller airways called bronchioles.
• Bronchioles lack cartilage and submucosal glands.
• These bronchioles further lead to terminal brionchioles
• The "acinus", the most distal part, is composed of alveolar ducts and sacs.
• It is the capillaries surrounding the alveoli where respiratory gases are exchanged.

Alveolar Organization

• Alveolar septa are located between alveoli
• Moving from air to blood involves the alveolar epithelium, pulmonary interstitium, and capillary basement membrane
• The alveolar epithelium is a continuous layer of two cell types.
• Type I pneumocytes cover 95% of the alveolar surface.
• Type II pneumocytes repair alveolar epithelium when damaged and create surfactant.
• The pulmonary interstitium contains elastic fibers, mast cells, and other miscellaneous cells and tissues.

Atelectasis

• Atelectasis, also known as lung collapse, shouldn't be confused with pneumothorax
• Atelectasis refers to a loss of lung volume due to inadequate airspace expansion.
• The basic principle of atelectasis is "use it or lose it"
• After the precipitating factor, physiologic "shunting" of blood occurs, which moves blood from poorly perfused areas to elsewhere

Types of Atelectasis

• Contraction atelectasis is when fibrosis hampers lung expansion
• Resorption atelectasis is when obstruction impairs air from reaching distal airways, as can happen post-thoracic surgery, or foreign body aspiration.
• With resorption atelectasis, any trapped air gets absorbed
• Compression atelectasis occurs when fluid, blood, or air accumulates within the pleural cavity.
• Atelectasis from failure to breathe deeply stems from pain or neuromuscular disease

ARDS Definition

• ARDS characterizes as respiratory failure within one week of a known clinical insult
• It presents as bilateral opacities on chest imaging not fully explained by effusions, atelectasis, cardiac failure, or fluid overload.
• 85% of ARDS cases arise within three days, in some occasions within 30 minutes

Key Features of ARDS

• ARDS causes the rapid onset of life-threatening respiratory insufficiency
• Integrity of the alveolar-capillary membrane is compromised by endothelial and epithelial injury
• The causes are infections or an exposure to caustic substances
• Injury leads to inflammatory reactions
• Cytokines are synthesized, along with neutrophil chemotaxis, interlukin 1 and TNF
• Neutrophils accumulate in pulmonary capillaries
• Neutrophils occupy vascular space, the interstitium, and alveoli
• Neutrophils release caustic products: ROSS (Reactive Oxygen Species) and proteases
• Vascular leaking and loss of surfactant ensue
• Fluid accumulates in the airspaces, inhibiting oxygen diffusion
• ARDS is associated with refractory hypoxemia

ARDS Chronology

• Patients who survive ARDS can take six to twelve months to return to normal pulmonary function.
• Long-term lung damage occurs in 25% of ARDS cases.
• Type II pneumocytes proliferate to regenerate the alveolar lining
• The proliferation of interstitial cells and deposition of collagen triggered by macrophages leads to fibroblasts
• Fibrin-rich exudates organize into interalveolar fibrosis, leading to the thickening of alveolar septa and poor gas exchange
• Noncompliant and less expansive lungs lead to chronic lung disease.

ARDS in Brief

• Cytokines can lead to neutrophil sequestration and activation
• PMNs release their products
• Hyaline membrane formation is observed
• Macrophage-derived fibrogenic cytokines occur
• ARDS can occur in several different clinical settings, particularly those with severe systemic inflammatory disorders
• Common ARDS triggers include PNA (35-45%), sepsis (30-35%), aspiration, trauma, pancreatitis, and transfusion reactions.

Obstructive vs. Restrictive Pulmonary Disease

• Obstructive diseases increase resistance to airflow, measured by blowing out with difficulty
• Restrictive diseases cause reduced lung expansion and decreased total lung capacity
• In obstructive disease, forced vital capacity (FVC) is normal, but the expiratory flow rate (FEV1) is significantly decreased
• In restrictive disease, the FVC is reduced, and the expiratory flow rate is also reduced
• Examples of obstructive pulmonary issues include emphysema, chronic bronchitis, asthma, and bronchiectasis.

Obstructive Diseases Types

• Chronic bronchitis involves large airways
• Emphysema affects the acinus
• Asthma is a disease of bronchospasm
• Bronchiectasis involves the scarring of the airways
• COPD features emphysema and chronic bronchitis
  • These two diseases intermingle in long-term smokers
• Emphysema by itself is possible, particularly among those with alpha-1 antitrypsin disorder

Emphysema Definition

• Emphysema describes permanent enlargement of air spaces distal to terminal bronchioles with destruction of the walls and significant fibrosis.
• The two clinically significant types of emphysema are centriacinar and panacinar.
  • Centriacinar emphysema affects the central/proximal parts of acini, while distal alveoli are spared
  • Panacinar affects the acini uniformly and is associated with alpha-1 antitrypsin deficiency

Emphysema Pathology

• Cigarette smoke causes lung damage and inflammation
• inflammatory mediators are released and they promote the recruitment of inflammatory cells
• With alveolar loss, acinar damage ensues, causing bulging of the acinus and alveoli
• The number of alveolar capillaries diminishes
• Diffusing capacity and gas exchange are reduced
• Without elastic tisse, small ainways collapse during expiration leading to outflow obstruction

Emphysema and alpha-1 Antitrypsin

• Alpha-1 antitrypsin is normally present in serum, tissue fluids, and macrophages which inhibits elastase
• In genetic disease, the lungs and liver are affected
• The acinus is affected with normal emphysema

Emphysema Symptoms

• Dyspnea is the primary symptom
• Disease is compensated for with hyperventilation
  • Hyperventilation leads to increased energy demands and profound weight loss, which can result in reduced caloric intake
• Physical exam may reveal tachypnea, pursed-lip breathing, hunched posture, and a barrel chest
• Secondary effects can include pulmonary hypertension, physiologic shunting, obstructive overinflation, expansion of the lung due to air trapping, and bullae

Chronic Bronchitis Pathology

• Chronic bronchitis features a persistent productive cough for 3 consecutive months lasting at least 2 consecutive years
• Cigarette smoke induces hypertrophy of mucous glands in the trachea and bronchi and transcription of the mucin gene
• There is also an increase in mucin-secreting goblet cells in the epithelial surfaces of small bronchi and bronchioles.
• Inflammation leads to mucous plugging of the bronchiolar lumen
• Local tissue destruction and fibrosis can occur
• PMNs and macrophages are observed, but not eosinophils, which are the hallmark of asthma

Chronic Bronchitis Sequelae and Symptoms

• Sufferers of severe bronchiolitis can experience complete fibrotic obstruction, termed "bronchiolitis obliterans“
• Early-stage cough raises mucoid sputum, but patients may have hyperreactive airways
• Late-stage findings may include outflow obstruction and its sequelae
• Hypercapnia from a failure to blow off CO2 or hypoxemia from a failure to inhale oxygen may be observed
• Pulmonary hypertension leads to additional issues
• COPD patients with bronchitis have more rapid disease progression and poorer outcomes than those with isolated emphysema.

Smoking Damage

• Long term, cigarette smoke recruits neutrophils and promotes transcription of mucin genes
• Acini are damaged and Inflammation and fibrosis arise
• Mucus plugging of the bronchial lumen is likely
• Significant disease overlap in both types of COPD arises due to long-term smoking

Asthma Types

• Asthma is a chronic inflammatory disorder characterized by intermittent and reversible airway obstruction, chronic bronchial inflammation with eosinophils, bronchial hypertrophy, and hyperreactivity
• Atopic asthma features hypersensitivity type I
• Non-atopic asthma does not feature hypersensitivity

Atopic Asthma Pathology

• Excessive helper T cell activation releases cytokines
• Interleukins 4,5, and 13 are likely
• Coated mast cells encounter antigen and release histamine with with pro-inflammatory prostaglandin and leukotrienes
• Inflammation prompts epithelial cells in the lung to attract eosinophils
• Repeated inflammatory leads to airway remodeling, including hypertrophy of bronchial smooth muscle, increased mucus glands, and increased vasculature
• Structural changes result in an irreversible component in the late stage

Non-Atopic Asthma Pathology

• In non-atopic asthma, allergen sensitization and skin tests for offending agents are negative
• Viral illnesses or air pollutants may trigger attacks, and the same inflammatory mediators function as in atopic asthma
• Treatment for atopic and non-atopic asthma don't vary
• A family history is less likely

Asthma Symptoms

• Asthma produces recurrent episodes of wheezing, breathlessness, chest tightness, and cough, particularly at night
• In atopic asthma, triggers my include pollen, dust, animal dander, or food
• The onset of an asthma attack may be preceded by rhinitis, urticaria, or eczema

Asthma Attacks

• Severe dyspnea, bronchoconstriction, and mucus plugging cause wheezing, coughing, and air trapping
• Attacks typically last from one to several hours, which can result in hypercapnia or fatality
• X-rays are typically normal
• When attacks go untreated or are resistant, this is known as status asthmaticus

Asthma Treatment

• Treatment focuses on targeting underlying processes
• Bronchodilators/beta-adrenergic drugs, anti-inflammatories/steroids and leukotriene inhibtors are often used

Bronchiectasis

• Bronchiectasis describes the permanent dilation of bronchi and bronchioles from destruction of smooth muscle and elastic tissue
• Obstruction or from chronic/necrotizing infection
  • Obstruction is common for foreign body/ tumors. Superimposed infection may also arise.
• Cystic fibrosis may also cause bronchiectasis
• Inflammatory damage and fibrosis enalrge the bronchi and bronchioles

Bronchiectasis Symptoms

• Severe persistent cough is characteristic, along with expectoration of sputum that may be fetid
• Symptoms correlate with new infections

Idiopathic Pulmonary Fibrosis

• Idiopathic pulmonary fibrosis describes patchy, progressive bilateral interstitial fibrosis and resultant restriction
• The etiology is unclear but may be genetic and environmental
• It is linked to mutations in MUC5B and surfactant genes only expressed in the lung
• It is also linked to loss of telomerase and cell senescence, more common among people 50+
• A connection to GERD has been noted, which may be from repeated cellular injury

Idiopathic Pulmonary Fibrosis Symptoms

• The sufferer is male and older, with a chronic, nonproductive cough and dry crackles
• Late-stage implications feature "honeycombing”

Other Fibrotic diseases

• Nonspecific interstitial pneumonia is a less severe form of idiopathic pulmonary fibrosis
• Cryptogenic organizing pneumonia sometimes resolves spontaneously

Pneumoconioses

• Pneumoconioses describe the accumulation of environmental particulate in the lung leading to disease
• The major causes are anthracosis (coal), silicosis, and asbestosis
• 10 micrometers particulate too big to get to distal airway and lodged in the bifurcations or removed through ciliary motion
• 0.5 micrometers will pass to alveoli and move out from it
• 1–5 micrometers will accumulate and cause problems

Pneumoconioses Pathology

• 1–5 micrometer particulate traps in distal lung in alveolar duct bifurcations
• Macrophages engulf the trapped particles
• This initiates an inflammatory response resulting in fibroblasts proliferating
• Cells drain to lymphatics amplifying immune response through adaptive system

Anthracosis

• Coal Worker's Pneumoconiosis is Anthracosis
• Macrophages engulf carbon pigment and connect to pulmonary and pleural lymphatics
• Simple CWP is triggered from macules and nodules
• Complicated CWP has multiple dark scars at 2-10 cm in length and is often worsened by pulmonary hypertension

Silicosis

• Silicosis is the most prevalent chronic occupational disease in the world and stems from sandblasting and hard-rock mining
• Quartz, crisobalite, and tridymite causes deposition in epithelial cells and progresses to both fibrosis and pulmonary hypertension

Asbestosis

• Asbestosis features fibers deposited in lungs and eaten by macrophages and creates inflammation and fibrosis
• Key risks are pleural effusions, and lung carcinoma
• There may be laryngeal carcinoma
• The risk for cancer increases with smoke inhalation

Sarcoidosis

• Sarcoidosis manifests as a noncaseating granulomas and is multisystemic.
• It can manifest as noncaseating granulomas in various tissues and typically affects the lungs in ~90% of cases
• Liver involvement and formation of granulomas and interstitial fibrosis may also occur
• Manifestations also include increased calcium-levels from Vitamin D release as well cough and skin lesions.

Hypersensitivity Pneumonitis

• Hypersensitivity pneumonitis describes lung disease primarily affecting the alveoli that is immunologically mediated
• Can occur in conjunction with dairy farms or metalworking fluids

Pulmonary Embolus

• Almost all large pulmonary artery is embolic originating from lower leg veins
• Prolonged bed rest or cancer may pose greater risk for pulmonary and genetic disorders
• Pulmonary infarct can cause heart failure or sudden death

Pulmonary Hypertension

• Defined by pressures of 25 mm Hg or more at rest and less commonly by increased pulmonary vascular blood flow
• Pulmonary arterial is from connective diseases, and pulmonary hypertension comes from disease
• Dyspnea and fatigue come from pulmonary hypertension
• Chronic patients see cyanosis

Pneumonia Definition

• Pneumonia is any infection in the lung in the alveolar spaces, and it represents 1/6 of all deaths
• Pneumonia types include
• Community Acquired Bacterial Pneumonia
• Community Acquired Viral Pneumonia
• Nosocomial Pneumonia (hospital acquired)
• Aspiration Pneumonia
• Chronic Pneumonia
• Necrotizing Pneumonia & Lung Abscess
• Pneumonia of the Immunocompromised patient

Pneumonia Bacteria

• The most common bacterial causes, in community-acquired infections
  • S. Pneumoniae
  • H. Influenzae
  • S. Aureus
  • K. pneumoniae
  • P. Aeruginosa
• Bacterial pneumonia features red hepatization

Viral Pneumonia

• Viral features respiratory distress that's out of proportion to the clinical and radiologic signs
• Common viruses for pneumonia
• Covid-19
• Influenza A
• Influenza B

Acute Pneumonia Signs

• Signs may include
  • Abrupt start
  • High fever
  • Shaking
  • Pleuritic chest pain
• Productive cough
• Rapid breathing

Pulmonary Complications

• Pulmonary complications from pneumonia is the spread to the visceral surfaces.
• Damage may come to the lung from
  • Abcess and empyema
  • Bronchiectasis
  • Interstitial fibrosis

Tuberculosis Overview

• Caused by Mycobacterium
• TB is airborne and effects the lugs
• The center causes caseous necrosis
• TB lands along lung fissures and exterior side of lung at first, which will result in primary TB if left alone
• Active immune system is needed to prevent TB infection
• "secondary TB” is when TP occurs in lung apices

Primary Tuberculosis

• Lung infection and regional lymph nodes
• Will calcify to Ghon
• 5% newly infected will acquire diease
• For bacteria -Death of tb
• Goes dormant
• Divisions occurs

Secondary Infection

• Pulmonary cavities are from infection that creates a granulomatous spread
• Will see cavitation

General TB Info

• Typically has malaise and coughing
• Could cause issues, low fever or lose appetite
• Tested with acid-fast stains
• This will help give a diagnosis
• If not taken proper care this can be life threating

Lung Cancer - General Info

• The most common form of fatal cancer
• Carcinogens are an important risk factor
• 95% of primary tumors is lung cancer
• Two forms small cell and large cell cancer

Lung Subtypes

• Adenocarcinoma (most common-slowest growing)
• Squamous cell carcinoma -Invariably produce bronchial obstruction
  • Leads to pneumonitis
• Small Cell, Including Oat Cell
  • Paraneoplastic syndromes
  • Many produce neurosecretory issues
  • This includes too much or too little hormone
• Large Cell Carcinoma
• Diagnosis by removal of exclusion

Lung Cancer Diagnosis

• Can look at early stage lung cancer.
• Coughing and exhalation are the two steps
• This will produce metastasis spreads

Paraneoplastic Syndrome

• Related to increase calcium and Pth hormones
• Can occur by increase in -Acth production
  • Increase in adh

Malignant Mesothelioma

• Rare CA of the mesothelial cells from lung
• Latent periods are 2-40 years
• Causative mutation are
  • As bestos material/ toxic compound
  • Causative Driver mutation
  • Can damage liver or splean

Pleural Effusion

• Most damage is chest/or in the pleural
• Transudate > hydrothax -Most common causes are CHF
• Cancer is the infection cause

Cystic Fibrosis Info

• Cf auto dominate cause from -Mutation in the cyst
  • Protein chloride
  • Lung , pancreas, sweat glands and vas def
• CF has features that --Involving with chloride production
  • Pancreatic secretion
• Mucos leads to blockage and viscous mucus
• Hard to function and causes secretion blockings

Cystic Fibrosis and Pathogenesis

• Bacteria initiate an inflammatory system Dehydrated and viscous secretions creates problems in the lugs
• This leads to poor air flow in the lungs Loss of transport to the pancreatic duct

General Cystic Fibrosis

• Symptoms lead to excess sodium level in testing,
• Poor natural history involving 4/% of patients are diagnosed at a adult level
• Meconium leus is tested by increased levels of calories

Cystic Fibrosis and Health

• 94% of male suffers are infertile
• Environmental factors are major factors
• In those affected with this one must used -Physical therapy and treatment are needed like mucolytic acids
• Those infected, carriers are likely to spread 1 in 50