Lung Development and Airways

Lung Development:

• The respiratory system arises as an outgrowth from the foregut’s ventral wall.
• The midline trachea develops two lateral lung bud outpouchings.
• The right lung bud divides into three main bronchi, while the left divides into two, resulting in three right lobes and two left lobes.

Lung Airways

• Main bronchi branch into smaller airways called bronchioles, lacking cartilage and submucosal glands.
• Further branching leads to terminal bronchioles, and the lung distal to these is the acinus.
• Pulmonary acini consist of respiratory bronchioles branching into alveolar ducts, which then branch into alveolar sacs.

Alveolar Walls & Cells

• Alveolar walls consist of capillary endothelium and basement membrane, the pulmonary interstitium and alveolar epithelium.
• The pulmonary interstitium has fine elastic fibers, collagen bundles, fibroblast-like cells, smooth muscle cells, mast cells, and rare mononuclear cells.
• Alveolar epithelium has type I pneumocytes (covering 95% of the alveolar surface) and rounded type II pneumocytes which synthesise pulmonary surfactant and repair alveolar epithelium.
• Alveolar macrophages reside within the alveolar space.

Lung Diseases

• Lung diseases are divided into those affecting the airways, the interstitium, and the pulmonary vascular system.

Atelectasis (Collapse):

• Lung collapse is caused by inadequate air space expansion.
• Resulting in shunting of inadequately oxygenated blood and a ventilation-perfusion imbalance, causing hypoxia.
• Classified into three forms: resorption, compression, and contraction.

Resorption Atelectasis:

• Occurs when airway obstruction prevents air from reaching distal airways.
• Air is absorbed causing alveolar collapse.
• Bronchial obstruction is the most common cause, often postoperatively due to mucous plugs.

Compression Atelectasis:

• Associated with fluid, blood, or air accumulation in the pleural cavity.
• Pleural effusions from congestive heart failure are a frequent cause.

Contraction Atelectasis:

• (Cicatrisation atelectasis) occurs when lung or pleura fibrosis hampers lung expansion.

Treatment of Atelectasis

• Atelectasis can be reversed, except when due to contraction.
• Needs prompt treatment to prevent hypoxemia and superimposed infection of the collapsed lung.

Acute Respiratory Distress Syndrome (ARDS):

• Respiratory failure occurs within 1 week of a clinical insult.
• Bilateral opacities occur on chest imaging, not fully explained by effusions, atelectasis, cardiac failure, or fluid overload.
• Severity is graded based on changes in arterial blood oxygenation.
• Usually leads to extensive bilateral injury to alveoli.

Severe ARDS:

• Characterized by rapid onset of respiratory insufficiency, cyanosis, and severe arterial hypoxemia.

Histological Manifestation

• Histologically known as diffuse alveolar damage (DAD).
• Associated with primary pulmonary diseases and severe systemic inflammatory disorders like sepsis.
• Pneumonia (35-45%) and sepsis (30-35%) are the most frequent triggers of ARDS, then aspiration, trauma and pancreatitis.
• ARDS is distinct from respiratory distress syndrome of the newborn, which is caused by surfactant deficiency due to prematurity.
• In ARDS alveolar-capillary membrane integrity is compromised through endothelial and epithelial injury.
• ARDS stems from an inflammatory reaction, initiated via pro-inflammatory mediators.
• Interleukin 8 (IL-8) by pulmonary macrophages synthesis increases as early as 30 minutes after an acute insult.

Role of Cytokines & Neutrophils in ARDS

• Release of IL-8, IL-1, and tumour necrosis factor (TNF) leads to neutrophil activation and sequestration in pulmonary capillaries.
• Neutrophils play an important role.
• Histologic examination shows increased numbers of neutrophils.
• Damage occurs via reactive oxygen species and proteases, causing vascular leakiness, which leads to surfactant loss and alveolar unit incapability.

Counteracting the Effects of Neutrophils

• Endogenous antiproteases and antioxidants, upregulated by proinflammatory cytokines counteract the Destructive forces.
• The balance between destructive and protective factors determines tissue injury and ARDS clinical severity.

Clinical Features of ARDS

• Develops within 72 hours of initial insult.
• Predictors of poor prognosis: advanced age, sepsis, and multiorgan failure development.
• Most patients with acute insult recover normal respiratory function within 6–12 months, while others develop diffuse interstitial fibrosis, which leads to chronic respiratory insufficiency.

Morphology of ARDS

• In the acute phase, the lungs are dark red, firm, airless, and heavy.
• Capillary congestion, alveolar epithelial cell necrosis, interstitial and intraalveolar edema and haemorrhage, and neutrophil collections in capillaries are revealed.
• Hyaline membranes, lining distended alveolar ducts consist of fibrin-rich edema fluid mixed with necrotic epithelial cell remnants.
• Resolution is unusual, fibrin-rich exudates organize into intraalveolar fibrosis, while Marked alveolar septa thickening ensues with interstitial cell proliferation and collagen deposition.

Obstructive (Airway) Disease

• Increased resistance to airflow, caused by partial or complete obstruction.

Restrictive Disease

• Reduced lung parenchyma expansion and decreased total lung capacity.

Obstructive Disorders

• Include emphysema, chronic bronchitis, bronchiectasis, and asthma.
• Forced vital capacity (FVC) is normal or slightly decreased.
• Expiratory flow rate measured as the forced expiratory volume at 1 second (FEV1), is significantly decreased resulting in a characteristically decreased FEV1 to FVC ratio.
• Expiratory obstruction may result from anatomic airway narrowing, classically observed in asthma, or from loss of elastic recoil, characteristic of emphysema.
• Diffuse restrictive diseases lower FVC and the expiratory flow rate is normal or reduced proportionately. The FEV to FVC ratio is near normal.

Restrictive Defects

• Include chest wall disorders with normal lungs and acute or chronic interstitial lung diseases. The classic acute restrictive disease is ARDS.

Obstructive Lung (Airway) Diseases

• 4 disorders: emphysema, chronic bronchitis, asthma and bronchiectasis.
• Emphysema (affects acinus), chronic bronchitis (involves large airways), asthma and bronchiectasis (small airways).
• Emphysema is defined on the basis of morphologic and radiologic features, whereas chronic bronchitis is defined on the basis of clinical features.
• Emphysema may exist without chronic bronchitis (particularly in inherited a1-anti-trypsin deficiency) and vice versa, the two diseases usually coexist.
• Cigarette smoking is the major underlying cause.

COPD Characterisation

• Emphysema and chronic bronchitis are often grouped under chronic obstructive pulmonary disease (COPD) because of their propensity to coexist.
• COPD is largely irreversible airflow obstruction that distinguishes from asthma, which is characterized by reversible airflow obstruction.

Emphysema

• Characterized by permanent enlargement of air spaces distal to terminal bronchioles.
• Destruction of walls occurs absent significant fibrosis.
• Classified according to anatomic distribution.

Emphysema Types

• Includes Centriacinar, Panacinar, Distal acinar and Irregular.

Emphysema Cause of Obstruction

• Only the first two types cause significant airway obstruction.
• Centriacinar emphysema is 20 times more common than panacinar disease.

Centriacinar emphysema

• Central or proximal parts of of the acini are affected.
• Affecting respiratory bronchioles, while distal alveoli are spared.
• Emphysematous and normal air spaces exist within same acinus and lobule.
• Upper lobes are more common.
• Occurs in cigarette smokers and is often associated with chronic bronchitis.

Panacinar emphysema

• Uniformly enlarged acini occur from the respiratory bronchiole level to terminal alveoli.
• Occurs more commonly in lower lung zones and is associated with a1-anti-trypsin deficiency.

Distal acinar emphysema

• Proximal portion of acinus is normal.
• Distal part is primarily involved.
• More striking adjacent to pleura, along lobular connective tissue septa, and lobules margins. Occurs adjacent to fibrosis, scarring, or atelectasis.

Irregular emphysema

• Is invariably associated with scarring.
• It may be the most common form of emphysema.

Emphysema Pathogenesis

• Cigarette smoke causes lung damage and inflammation.
• Results in parenchymal destruction (emphysema) and airway disease (bronchiolitis and chronic bronchitis) with a genetic predisposition.

Factors Influencing Emphysema Development

• Inflammatory cells and mediators: Increased inflammatory mediators including leukotriene B4, IL-8, TNF, etc).
• Inflammatory cells present: neutrophils, macrophages and CD4+ and CD8+ T cells.

Protease-antiprotease imbalance

• Inflammatory and epithelial cells release proteases that break down connective tissues.
• People with emphysema suffer a relative deficiency of protective anti-proteases.

Oxidative stress

• Reactive oxygen species are generated by cigarette smoke and other inhaled particles released from activated inflammatory cells.
• This causes additional tissue damage and inflammation.

Airway infection

• Not thought to play a role in tissue destruction initiation, but bacterial and viral infections may cause acute exacerbations.
• a1-antitrypsin is a major protease inhibitor that is encoded by a gene in the proteinase inhibitor (Pi) locus on chromosome 14.
• More than 80% of these individuals develop panacinar emphysema.
• Protease-mediated damage of extracellular matrix has a central role in airway obstruction seen in emphysema. Small airways are normally held open by the elastic recoil of the lung parenchyma
• Loss of elastic tissue in alveoli walls surrounding respiratory bronchioles reduces radial traction causing the bronchioles to collapse during expiration.

Features of the Lung and Emphysema

• It is difficult to diagnose and classify through morphology.
• Typical panacinar emphysema produces pale, voluminous lungs that often obscure the heart when the anterior chest wall is removed at autopsy, centriacinar emphysema is less impressive.
• Until late stages, centriacinar emphysema the lungs are deeper pink than in panacinar emphysema and less voluminous.
• Upper two-thirds of the lungs are more severely affected, Destruction of alveolar walls without fibrosis, leading to enlarged air spaces.

Features of the bronchioles in Emphysema

• Terminal and respiratory bronchioles may be deformed.
• Loss of tethering structures with surrounding parenchyma
• Contribute to chronic airflow obstruction in severe emphysema.
• Bronchiolar inflammation and submucosal fibrosis are consistently present in advanced disease.

Clinical Features of Emphysema

• Dyspnea is the first symptom and steadily progressive.
• Underlying chronic bronchitis or chronic asthmatic bronchitis patients present with initial complaints of cough and wheezing.
• Weight loss is common.

Pulmonary Function in Emphysema

• Reveals reduced FEV1 with normal or near-normal FVC.
• Results in FEV1 to FVC ratio reduction.

Pink Puffer

• Classic presentation of barrel-chested and dyspneic emphysema, with no ‘bronchitic’ component, prolonged expiration, sitting forward in hunched position with severe space enlargement.
• Gas exchange is adequate and blood gas values are relatively normal until very late in disease.

Blue Bloater

• Emphysema with pronounced chronic bronchitis and recurrent infections.
• Dyspnea is less prominent, and retain carbon dioxide, become hypoxic and often cyanotic often.

Symptoms of Empysema

• Symptoms fall in between the two extremes.
• Hypoxia-induced pulmonary vascular spasm and capillary surface area loss from alveolar destruction
• Development of secondary pulmonary hypertension leads to right-sided congestive heart failure in 20% to 30% of persons affected.

Conditions Related to Emphysema

• Several conditions involve abnormal airspaces or air accumulations:
• Compensatory Emphysema: dilation of residual alveoli in response to lung substance loss.
• Obstructive overinflation: Lung expansion due to air trapping; common cause being subtotal airway obstruction.

Bullous Emphysema

• Form that produces large subpleural blebs or bullae.
• Localized one of the four emphysema forms, most often subpleural.

Mediastinal Emphysema

• Interstitial: Entry of air into lung interstitium may track to mediastinum and subcutaneous tissue.
• Intraalveolar pressure (emesis or violent coughing) may spontaneously lead to rupture

Chronic Bronchitis:

• Defined as persistent coughing with sputum for 3+ consecutive months in 2 consecutive years.
• It is Postulated that many of the effects of environmental irritants on respiratory epithelium are mediated by local release of cytokines.
• The transcription of the mucin gene in bronchial epithelium and the production of neutrophil elastase are increased as a consequence of exposure to tobacco smoke.
• Microbial infection often is present but has a secondary role, chiefly by maintaining inflammation and exacerbating symptoms.

Morphology:

• Gross specimens show mucosal lining of larger airways is hyperemic, swollen with edema, and is covered by mucinous secretions.
• Smaller bronchi and bronchioles also often filled with secretions, diagnostic feature of enlarged mucus-secreting glands.
• Variable number of inflammatory cells are largely lymphocytes and macrophages but sometimes also neutrophils are seen in the bronchial mucosa.
• Goblet cell metaplasia, mucous plugging, inflammation, fibrosis also are seen in severe cases; there may be complete obliteration of the lumen as a consequence of fibrosis. Emphysematous changes often coexist.

Morphology:

• Gross specimens show mucosal lining of larger airways is hyperemic, swollen with edema, and is covered by mucinous secretions.
• Smaller bronchi and bronchioles also often filled with secretions, diagnostic feature of enlarged mucus-secreting glands. Variable number of inflammatory cells are largely lymphocytes and macrophages but sometimes also neutrophils are seen in the bronchial mucosa.
• Goblet cell metaplasia, mucous plugging, inflammation, fibrosis also are seen in severe cases; there may be complete obliteration of the lumen as a consequence of fibrosis. Emphysematous changes often coexist.

###Clinical Features:

• Course of chronic bronchitis is quite variable. In some patients, cough and sputum production persist indefinitely without ventilatory dysfunction, while others develop COPD with significant outflow obstruction marked by hypercapnia, hypoxemia, and cyanosis.
• Progressiveness of the disease is marked by the development of pulmonary hypertension, which leads to cardiac failure; recurrent infections; ultimately respiratory failure.

Asthma

• It is the chronic inflammatory disorder affecting the airway causing recurrent episodes.
• Hallmarks: intermittent, reversible airway obstruction, with bronchial inflammation associated with bronchial smooth muscle hypertrophy, hyperactivity, and increased mucus secretion
• In some cases, trivial stimuli are sufficient to trigger attacks in patients because of airway hyper-reactivity.
• Cells such as eosinophils, mast cells, macrophages, lymphocytes, neutrophils, and epithelial play a role in the inflammatory response
• Asthma has increased remarkably in incidence significantly in the Western world over the past 4 decades.
• explanation for this troubling trend - hygiene hypothesis, according to which a lack of exposure to infectious organisms (and possibly nonpathogenic microorganisms as well) in early childhood results in defects in immune tolerance and subsequent hyperreactivity to immune stimuli later in life. genetic predisposition to type I hypersensitivity (atopy), as well as acute and chronic airway inflammation, and bronchial hyper-responsiveness to a variety of stimuli

Asthma Classification

• atopic (evidence of allergen sensitization), non-atopic.
• Episodes of bronchospasm may be triggered by exposures: respiratory infections (especially viral), airborne irritants, cold air, stress, and exercise.

Inflammation Patterns

• eosinophilic :most common
• neutrophilic and mixed inflammatory
• pauci-granulocytic -associated with the differing etiologies, immunopathologies, and responses to treatment.

Atopic Form of Asthma

• The atopic form is associated with excessive type 2 helper T (TH2).
• Cytokines of this type account for most features of atopic asthma.
  • IL-4 and IL-13 stimulate IgE production; IL-5 activates eosinophils; IL-13 also stimulates mucus production.
• IgE coats submucosal mast cells. Upon exposiure of the allergens granule releases contents as well as cytokines and other mediators.

Asthma Reaction

• There occurs 2 waves; Early or immediate and a late phase
• The early reaction phase is dominated by bronchoconstriction, increased mucus production and vasodilation.

Asthmatic Airway

• Accumulation of mucus in the lumen
• Hypertrophy of submucosal glands
• Intense chronic inflammation
• Thickened basement membrane is common
• Hypertrophy and hyperplasia of smooth muscle cells

Bronchiectasis:

• Bronchiectasis is dilation of bronchi and bronchioles caused by destruction of smooth muscle and its supporting elastic tissue; infection is often involved.
• It does not present as a primary disorder, but as a secondary disease derived from infections.

Major Causes of Bronchiectasis

• Obstruction is involved with foreign body, tumor and infection.
• Hereditary factors, can include cystic fibrosis
• Hereditary is often observed with cystic fibrosis

Pathogenisis

Can derive itself from either damage or obstruction

• Damage or obstruction leads to secretions as the result or damage will cause further distortion of the airways

Morphologies:

• Most often occurs on the bottom bilaterally
• Can get as wide as 4x their normal size.
• Histological aspects can be quite variable

Clinical Features:

• Involves cough and sputum production, along with other nasal infections

Chronic Interstitial Lung Diseases

• The diseases characterized by bilateral, patchy pulmonary fibrosis affecting alveolar walls
• Many of the entities of unknown causes
• The reduction of lung is a key component
• It can result in damage to epthelium
• It Can ultimately lead to a honey comb lung

Fibrosing Diseases

• Iodiopathic pulmonary fibers- The cause can be elusive to deteremine

Pathogenisis

• It is often a repeated injury
• injury to the epithelial surface

Morphological Features:

• Surfaces are cobblestoned due to septa
• Hallmark is a patchy interstitial fibrosis along with a presence of a "fribrotic focus".
• Eventually can appear as a honey comb

Clinical Features:

• Causes: Non productive cough and progressive dyspnea can lead to cyanosis.
• Characteristic clinical radiologic findings can be used to diagnose-The lung can be damaged due to various outside compounds
• Can result in silicosis and asbestosis

Pneumoconioses

• Include inhalation of mineral dust as well as vapor induced lung disorders and chemical fumes.

Pathogenisis:

• Size shape and solubility are important aspects
• Certain dust is easy to rid or can go further inside.
• Alveotlar Macrophage can be a big part in the damage process as well as inflamation

Coal Worker's Pneumoconiosis

• Worldwide reduction in coal dust in mines greatly as reduced the case.
• Can range from little damage to complete fibrosis.

Pathogenisis

• Inhaled pigment is taken into alveolar Macrophages
• Can be affected by emphysema
• Complicated from coalesence of noduels

Clinical Features:

• Damage can range from little to a decremented lung
• Can lead to cor-pulmonae.

Silicosis

• Mostly related to workers in sandblasting and hard rock mining.
• Most associated with crystalized forms

Pathogenisis:

• The ingested silica activates an inflammasome and subsequent releases.
• The process reduces the quartz

Morphological Findings

• In upper zones of lungs and can be discrete is early staging
• Appear as though it is a silicotic nodule of organized collagen.

Clinicals

• Can show on asympomatic x rays.
• Shortness of breath will not occur until late
• The disease often impairs physical activity

Silicosis Relation with TB

• Association with TB.
• Appears the it lowers the function of the cell mediated immunity
• relationship with lung cancer and silica is inconclusive

Asbestosis

• Asbestos is linked to interstitial Fibrosis
• Increased the chance of getting many kinds of related cancers

Pathogenisis:

Asbestos is activated and damages a phageolysosomal.

• These actions can also act as possible tumor growth
• The fibers in the lungs interact with carcinogens

Morphological Features

• Causes plumonary interstitial fibrosis and is found in beaded rods
• It is derived from pphagocyte Ferritin
• The process begins in the lower lungs and will spread upward

Clinical Results:

• Causess Dyspnea

Lungs:

• Are affected by a variety of structure that can be induced by drugs.
• Bleomycin causes pneumonitis
• Amiodarone is a arrhythmic that could be dangerous
• Pneumonitis causes fever and can be associated with the lung

Granulomatous Diseases

• Affects the entire structure
• Can be accompanied by multisystem and in the restritiv lung

Epidemiology

• Can be apparent under 40 years of age
• Higher in smokeless people

Etiology and Pathogenisis

Related to T cells

• CD4 and Th1 related

Morphology

• Histological Features
• CD4 1cells
• Can be lung transplants

The Progression of Granuloma

• It is replaced by diffusion
• Can affect different parts of the body of equal parts.

Clinical Features:

• Discovered as people are asymptomatic, the diagnosis will include clinical radiologic tests.
• The 60 -70% recover with a low amount permanently damaged

Hypersensitivity Pneumonitis

• An immunologically mediated inflam lung
• It is an restrictive lung disorder
• Specimens of Bronchoaveli consistently show many parts of T
• Patients have antibidied against specific antigens

Pulmonary Eiosinophilia

• Eiosinphilais that are recruited to the lung when chematactic factors are present

Smoking Related Interstitial Diseases

• DIP happens by those with dust color pigments

Pulmonary Disease of Vascular Origin

• Consequences depend on parts of lungs affected
• Increased pressure from blood vessels can be from vaso spasms

Pluminary Hypertension

• Divided into parts
• Plumonary has to co me from left sided damage

All forms are related but:

They are medial

• Results in hypertrophy
• Cunical Features are chest pain and dizziness

Goodpasture syndrome

It’s an autoimmune disease. The problem is that it affect both lungs and kidney,

Lungs

• There will abundant Hemocdrin

Granulomatosis and polyangitits

Involves necreating and inflammation

• Signs and Symptoms steam from the upper respiratory tract with the lungs

Pnemonias

• Divided to bacterial and brocho
• Pactchy consilidation is the brocho kind.
• Grey happens as red cells are disintegration

Lung Abscess

• Anaerobic and bacteria that is in the lung
• It will yield a lot of bloody foul smelly sputum. And results also with fever of common

Turberoclisis

Communicating and granulous and most deadly for infectious origin.