Lungs: Metabolic Function

Introduction

• The lungs do more than exchange oxygen and carbon dioxide.
• They act as metabolic organs that modify circulating molecules, affect systemic vascular tone, and influence drug activity.
• These functions are possible because of their large endothelial surface area and exposure to the entire cardiac output.

Angiotensin Conversion¹

• Pulmonary endothelial cells express angiotensin-converting enzyme (ACE) on their surface (Figure 1). ACE catalyzes the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor with multiple systemic effects:
  • Increases systemic vascular resistance (SVR) and helps maintain arterial blood pressure.
  • Stimulates aldosterone release from the adrenal cortex, resulting in sodium and water retention.
  • Enhances sympathetic activity, further contributing to vasoconstriction and cardiac output.
• Clinical Implication: ACE activity is affected by lung injury/endothelial damage.
  • In inflammatory/septic lung injury, endothelial cells may lose surface ACE due to both damage and shedding, reducing local ACE activity.
  • Consequences: Reduced angiotensin II production leads to refractory hypotension, while bradykinin accumulation causes vasodilation, vascular leak, and potential angioedema.

Inactivation/Uptake of Vasoactive Substances

• Because a large portion of cardiac output passes through the pulmonary circulation, the lungs act as a major control point for substances that influence vascular tone, inflammation, and hemodynamics.
• The lungs prevent sudden systemic effects that would otherwise cause large swings in blood pressure or vascular permeability by degrading or inactivating these molecules:

Bradykinin²

• Physiologic effects of bradykinin:
  • Vasodilation: Bradykinin binds B2 receptors on vascular endothelial cells, stimulating the production of nitric oxide and prostacyclin. This leads to smooth muscle relaxation and a reduction in SVR.
  • Increased capillary permeability: Bradykinin opens endothelial junctions, allowing fluid and proteins to leak into tissues, leading to edema.
  • Bronchoconstriction: Bradykinin activates B2 receptors on airway smooth muscle and sensory nerves, triggering local reflexes that cause acetylcholine release. This acetylcholine then narrows the airways, contributing to coughing or asthma-like symptoms.
• Degradation of bradykinin:
  • The lungs rapidly degrade bradykinin via ACE, preventing excessive systemic vasodilation and pulmonary edema (Figure 1).
• Clinical implication:
  • In patients taking ACE inhibitors, bradykinin levels increase, which can lead to cough, angioedema, and exaggerated vasodilation.

Serotonin³

• Serotonin Metabolism in the Lung:
  • The pulmonary endothelium is rich in monoamine oxidase (MAO) enzymes, which degrade circulating serotonin as blood passes through the lungs.
  • Most platelet-derived serotonin in the blood is metabolized in the lungs.
  • Serotonin is a strong pulmonary vasoconstrictor and can raise systemic blood pressure. By clearing serotonin, the lungs prevent sudden or excessive vasoconstriction, protecting pulmonary and systemic blood flow.
  • Serotonin reuptake inhibitors (SSRIs) block serotonin reuptake via the serotonin transporter (SERT).
    • Chronic SSRI use has been associated with an increased risk of developing pulmonary hypertension, especially in susceptible individuals.
• Serotonin Synthesis in the Lung:
  • Some lung cells can synthesize serotonin locally:
    • Pulmonary endothelial cells and neuroendocrine cells express tryptophan hydroxylase, the rate-limiting enzyme for serotonin synthesis.
    • Conditions such as hypoxia, pulmonary hypertension, and inflammation upregulate local serotonin synthesis.
    • Serotonin causes vasoconstriction and smooth muscle proliferation via serotonin receptors and SERT.
    • This promotes vascular remodeling and worsens pulmonary hypertension.

Prostaglandins⁴

• The lungs rapidly inactivate prostaglandins through a combination of enzymatic pathways located in the pulmonary endothelium. Without this clearance, prostaglandins would cause profound vasodilation and inflammation.
• Clinically, this is why drugs like alprostadil need continuous infusion, as they are removed efficiently when they pass through the lungs.

Norepinephrine⁵

• A portion of circulating norepinephrine (NE) is taken up by pulmonary endothelial cells. Within these cells, NE is metabolized by monoamine oxidase (MAO) and catechol-O-methyltransferase.
• Physiologic Role: This uptake and metabolism prevent excessive systemic vasoconstriction and overstimulation of the heart during stress or catecholamine surges.
• Clinical Relevance: In lung injury, endothelial dysfunction, or ARDS, NE metabolism is reduced, resulting in patients experiencing more unstable blood pressure or exaggerated responses to catecholamine drugs.

Surfactant Synthesis⁶

• Type II pneumocytes actively produce surfactant, which is a mixture of phospholipids, containing mostly dipalmitoylphosphatidylcholine (DPPC) and surfactant proteins (SP-A, SP-B, SP-C, SP-D).
• Surfactant has two essential functions:
  • Mechanical: DPPC lowers alveolar surface tension, preventing collapse during exhalation and maintaining alveolar stability and lung compliance.
  • Immunologic: SP-A and SP-D act as immune modulators, promoting pathogen clearance through opsonization and regulating alveolar inflammation.
• Clinical Relevance: A lack of functional surfactant plays a key role in the development of neonatal respiratory distress syndrome and contributes to alveolar instability and impaired gas exchange in acute respiratory distress syndrome (ARDS) (Table 1).

Drug Metabolism⁷

• Some medications undergo significant first-pass metabolism in the lungs before reaching systemic circulation.
  • This is due to the lungs’ large endothelial surface area, exposure to the entire cardiac output, and expression of drug metabolizing enzymes (CYP450s, esterases, and MAOs)
• The lungs act as a buffer for intravenous (IV) drugs, binding them and preventing acute rises in systemic circulation.
• After IV injection, propofol is partly taken up by the lungs, causing an initial rapid drop in plasma levels before redistribution.
• For inhaled or lung-targeted drugs, the lungs help determine how fast the drugs work, how long they last, and how much enters the bloodstream.
  • Budesonide and Fluticasone: Inhaled steroids are broken down in the lungs, reducing their effects elsewhere in the body.
  • Salmeterol and Theophylline: Partial lung metabolism controls how strong and how long their effects last.
• For systemic drugs that pass through the lungs, metabolism or uptake can affect onset, peak concentration, and duration, and can act as a buffer against sudden plasma changes.
  • Lidocaine (partial pulmonary uptake) and prilocaine (metabolized in the lungs)

Pulmonary Platelet Production^8,9

• The lung is now recognized as a major site of thrombopoiesis.
• Large megakaryocytes from the bone marrow travel through the pulmonary capillaries, where the narrow vessels mechanically fragment them into platelets (Figure 1). Research suggests that the lungs may contribute up to 50% of circulating platelets.
• Clinical significance: Lung injuries, such as ARDS, COVID-19, pneumonia, or trauma, can reduce platelet production, contributing to thrombocytopenia
• A recent experimental study using an ARDS animal model found that severe lung inflammation leads to lower platelet output from the lungs, despite an increased number of megakaryocytes.