Pneumothorax pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Feham Tariq, MD [2], Hamid Qazi, MD, BSc [3]

Overview

Pneumothorax is air in the pleural space under pressure resulting in lung collapse.The pathophysiology of each type depends on the underlying disease/etiology. Primary spontaneous pneumothorax most commonly results from the bleb (small air-filled lesions under pleural surface) rupture allowing the air to leak into the pleural space. A subclass of primary spontaneous pneumothorax is isolated familial primary spontaneous pneumothorax which is genetically associated with folliculin gene mutation. Secondary spontaneous pneumothorax occurs subsequent to underlying lung pathology such as obstructive lung disease, cystic fibrosis, diffuse parenchymal lung disease and lung cancer. In tension pneumothorax, the underlying pathophysiology most commonly is chest trauma forming a one-way valve in the pleura whereby air enters the pleural space when the pleural pressure is negative during inspiration. Pneumothorax can also result from several interventional procedures which cause penetrating or non-penetrating injury to the pleura resutling in abrupt increase in the alveolar pressure and hence, lead to alveolar rupture forming a communication with the pleura.

Pathophysiology

Anatomy and physiology of the thoracic cavity

The normal anatomy and physiology of thoracic cavity is as follows:

• Thoracic cavity is defined as the space inside the chest that contains the heart, lungs, and, several major blood vessels.

• On either side of the cavity, a pleural membrane covers the outside surface of the lung (visceral pleura) and also lines the inside of the chest wall (parietal pleura).
• The two layers are separated by a small amount of lubricating serous fluid known as the pleural fluid.
• The lungs are fully inflated within the cavity as the pressure inside the airways is higher than the pressure inside the pleural space.
• The inhaled air does not enter the pleural space as there is no natural connections between them as well as the pressure of gases in the blood stream is too low for them to be forced into the pleural space.
• The pleural pressure is negative with respect to atmospheric pressure during spontaneous breathing.
• Air can enter the pleural space through the following mechanisms:
  • Damage to the pleura or the chest wall
  • Damage to the lungs
  • Microorganisms in the pleural space

Pneumothorax Source:By National Heart Lung and Blood Institute, via Wikimedia Commons

Pathogenesis

The pathophysiology of pneumothorax depends on the underlying disease causing it.

Primary spontaneous pneumothorax

• The most common underlying pathology of primary spontaneous pneumothorax is an apical subpleural bleb (small air-filled lesions under the pleural surface).
• In addition, smoking causes inflammation and obstruction of the small airways, which is responsible for the increased risk of primary spontaneous pneumothorax in smokers.

Secondary spontaneous pneumothorax

• Pneumothorax due to underlying lung disease is secondary spontaneous pneumothorax.

Tension pneumothorax

• Tension pneumothorax develops when a disruption involves the visceral pleura, parietal pleura, or the tracheobronchial tree.

• The disruption occurs when a one-way valve forms, allowing air inflow into the pleural space, and prohibiting air outflow.
• The volume of this nonabsorbable intrapleural air increases with each inspiration.
• As a result, pressure rises within the affected hemithorax; ipsilateral lung collapses and causes hypoxia.
• Further pressure causes the mediastinum shift toward the contralateral side and compresses both, the contralateral lung and the vasculature entering the right atrium of the heart.
• This leads to worsening hypoxia and compromised venous return.

Iatrogenic pneumothorax

Following procedures commonly cause iatrogenic pneumothorax:

• Central cannulation
• Transthoracic needle aspiration
• Thoracocentesis
• Mechanical ventilation
• Thoracic acupuncture
• Transbronchial lung biopsy or transpleural intervention
• Intravenous drug abusers using neck veins
• Aggressive cardiopulmonary resuscitation

Mechanism of injury:

• Iatrogenic pneumothorax causes penetrating or non-penetrating injury to the pleura resulting in abrupt increase in the alveolar pressure, which can lead to alveolar rupture.
• Once the alveolus is ruptured, air enters the interstitial space and dissects toward either the visceral pleura or the mediastinum.
• A pneumothorax occurs when either the visceral or the mediastinal pleura ruptures that allows air to enter the pleural space.

Genetics

Genetic association of familial primary sponatneous pneumothorax

The genetic association of familial primary sponatneous pneumothorax is as follows:

• Primary spontaneous pneumothorax can result as a mutation in the FLCN (folliculin) gene.
• This gene codes for a protein called folliculin.
• It is produced by the cells lining the alveoli of the lung.
• Folliculin is found in the connective tissue cells that allow the lungs to contract and expand while breathing.
• It plays a role in repairing the lung tissue after damage.
• Nonsense mutation in the folliculin gene results in isolated familial sponataneous primary pneumothorax.
• Altered folliculin protein can trigger the inflammatory process within the lung tissue that can alter and damage the tissue, resulting in blebs formation.

Associated Conditions

Pneumothorax is associated with the following conditions:

• Homocystinuria
• Marfan's syndrome

Genetics

A defect in the gene TGFβR2 on chromosome 3, a receptor protein of TGFβ, has also been related to Marfan syndrome. Marfan syndrome can often be confused with Loeys-Dietz syndrome, a similar connective tissue disorder resulting from mutations in the TGFβ receptor genes TGFβR1 and TGFβR2.

Marfan syndrome is an autosomal dominant disorder caused by mutations in the Fibrillin-1 gene encoding an extracellular matrix protein which constitutes an essential component of microfibrils, critical in formation of elastin. Engvall first isolated the protein from human fibroblast cell culture in 1986, demonstrated its function as a component of extracellular microfibrils and its widespread expression through connective tissue in many organ systems . Early linkage studies of families with Marfan syndrome mapped the gene to 15q21.1 , surprising some investigators who suspected defects in the Elastin gene were causal. Subsequent mutational analysis of FBN1 in patients with Marfan system revealed identical missense mutations in two unrelated patients9. Many linkage studies have been performed and demonstrate that most families have private mutations. The FBN1 gene is very large, consisting of 65 exons. It encodes a 350 kiloDalton protein and is highly conserved between different species.

Familial mutations of the FBN1 gene account for 75% of cases of Marfan syndrome and their corresponding phenotype is inherited in a dominant fashion. Over 500 different FBN1 mutations have been detected in Marfan syndrome patients . 56% of these mutations are missense mutations, most often by creating or substituting a cysteine in a cbEGF domain critical for calcium binding . Missense mutations are clustered in loci with cbEGF domains and typically cause moderate to severe phenotype . Other documented mutations include nonsense, frameshift and splice site mutations. Complete deletions of a FBN1 allele are very rare. 90% of FBN1 mutations are private to an individual or family10. The incredibly diverse set of mutations that cause the syndrome suggest that these mutations generally reflect loss-of-function cause a dominant negative phenotype. Haploinsufficiency and other theories have been proposed to account for the dominant negative phenomenon which will be detailed later.

No FBN1 mutation can be identified in 10% of Marfan syndrome patients . In this subset of patients, mutations in the transforming growth factor-beta receptor 2 (TGFBR2) are causal. Families with TGFBR2 mutations display autosomal dominant inheritance with variable penetrance.

• Iatrogenic buffalo chest syndrome

Gross Pathology

On gross pathology, pneumothorax has the following findings:

• Bullae or blebs on the pleural surface

• Pleural fibrosis

• Pleuropulmonary adhesions

• Airway inflammation

Bleb Source:By Robertolyra (Own work), via Wikimedia Commons

Microscopic Pathology

• The microscopic findings associated with pneumothorax are as follows:
  • Pleural fibrosis with mesothelial thickening and hyperplasia.
  • Lymphocytes, eosinophils, mesothelial thickening, and proliferation of the pleura.

Lung Bleb Source:By Nephron (Own work) [CC BY-SA 4.0 via Wikimedia Commons