Lymphatic Drainage of the Lung

1. Overview and Functional Significance

• Murray & Nadel, Ch. 7

2. Structural Organization: Two Plexuses

A. Deep (Peribronchiovascular) Plexus

• Located in the peribronchovascular connective tissue sheaths
• Runs alongside airways (extending peripherally to the respiratory bronchioles), branches of pulmonary arteries, and pulmonary veins
• Within the lung, the vast majority of lymphatic vessels are in the interlobular septa or bronchovascular bundles
• Critically: no lymphatics in alveolar walls - casting studies and whole-mount immunohistochemistry have consistently failed to identify lymphatics in close association with alveoli in humans or rodents
• Murray & Nadel, Ch. 1 & Ch. 7

B. Superficial (Subpleural) Plexus

• Located in the connective tissue of the visceral pleura
• Particularly prominent in species with thick visceral pleura, including humans
• Visceral pleural lymphatics do NOT open into the pleural space and do NOT participate in pleural liquid clearance
• Collecting lymphatics in the periphery drain toward the visceral pleura but do not connect to the pleural space; centrally located lymphatics drain to the mediastinum
• Murray & Nadel, Ch. 1 & Ch. 7

3. Microstructure: Initial vs. Collecting Lymphatics

• Collecting pulmonary lymphatics in humans have only sporadic smooth muscle coverage (unlike collecting lymphatics elsewhere in the body which have robust smooth muscle lymphangions). This means the lung relies heavily on extrinsic forces - thoracic pressure changes during ventilation and cardiac pulsations - to propel lymph rather than intrinsic contractility.
• Murray & Nadel, Ch. 7

4. Direction of Lymph Flow and Regional Lymph Nodes

• Respiratory movements (changes in thoracic pressure during the ventilatory cycle)
• Heart pulsations

1. Intrapulmonary (segmental) nodes - within the lung parenchyma along bronchi
2. Hilar nodes (N1) - lobar and main bronchial nodes; within the pleural envelope (stations 10 and above on the Naruke map = extramediastinal)
3. Mediastinal nodes (N2) - subcarinal, paratracheal, and other mediastinal stations; true mediastinal nodes are stations 1-9 on the Naruke/IASLC map
4. Extrathoracic nodes (N3) - contralateral mediastinal/hilar, scalene, supraclavicular nodes

• Right lung (and left lower lobe in part): drains to the right lymphatic duct, which empties near the junction of the right internal jugular and right subclavian veins
• Left lung (upper lobe predominantly): drains into the thoracic duct, which empties near the junction of the left internal jugular and left subclavian veins

• Murray & Nadel, Ch. 1; Fishman's, Ch. 80

5. Pleural Lymphatics in Detail

Parietal Pleura

• The parietal pleura is the primary site of pleural fluid clearance
• Contains stomata: openings of 2-12 µm diameter formed by discontinuities in the mesothelial layer where mesothelium overlies the lymphatic endothelium
• Fluid, protein, and cells (including erythrocytes) exit via stomata → lacunae (spider-like submesothelial cisterns) → infracostal lymphatics → parasternal and periaortic nodes → right lymphatic duct or thoracic duct → central veins
• Carbon particle experiments confirm: carbon instilled into pleural space is taken up by parietal lymphatics, not visceral, confirming that only parietal lymphatics drain the pleural space

Visceral Pleura

• Has extensive lymphatics in the subpleural connective tissue layer
• These do not connect to the pleural space - no stomata on the visceral side
• Murray & Nadel, Ch. 14 (pleural space); Fishman's, Ch. 80

6. Lymphatic Reserve Capacity and Edema Prevention

• Baseline pleural lymphatic flow is slow (~0.01 mL/kg/hr in sheep)
• When fluid load increases, lymphatic drainage can increase ~30-fold (to 0.28 mL/kg/hr)
• This large reserve capacity is a key safety mechanism preventing pulmonary edema accumulation
• In the lung interstitium: imbalanced Starling forces drive fluid into the interstitium, but lymphatics actively clear it. Pulmonary edema occurs when the rate of fluid filtration exceeds lymphatic drainage capacity
• Lymphatics drain bulk flow (not diffusion): protein concentration remains constant as effusions resolve, which is the hallmark signature of bulk lymphatic clearance
• Murray & Nadel, Ch. 14

7. Lymphatic Endothelial Cell Markers

• PROX1 - master transcription factor and most reliable marker of lymphatic lineage
• VEGFR3 - useful in mouse lung; also expressed on blood endothelium in human lung
• Podoplanin - not specific in mouse lung (also on airway epithelium)
• LYVE-1 (lymphatic vessel endothelial hyaluronan receptor) - expressed by LECs but also on blood endothelium in mouse lung
• VEGF-C and VEGF-D are the principal lymphangiogenic growth factors signaling through VEGFR3
• Murray & Nadel, Ch. 7

8. Mediastinal Lymph Node Map (Naruke/IASLC Classification)

• Stations 1-9 = true mediastinal (N2 for ipsilateral involvement)
• Stations 10+ = extramediastinal/hilar (N1 for ipsilateral)
• Fishman's, Ch. 80

9. Clinical Correlates

Key Points Summary (Murray & Nadel, Ch. 7 Key Points)

• Very few lymphatics exist alongside alveoli in the normal lung
• Lymphatics are critical for fluid homeostasis and macromolecule drainage (including hyaluronan)
• Lymphatic endothelial cells identified by a panel of markers: podoplanin, VEGFR3, PROX1, LYVE-1
• Deep plexus: peribronchovascular; Superficial plexus: subpleural - communicate with each other
• Collecting pulmonary lymphatics lack robust smooth muscle; rely on respiratory mechanics for propulsion
• Lymph drains centripetally → hilar → mediastinal nodes → thoracic duct / right lymphatic duct → subclavian veins
• Parietal pleural stomata (2-12 µm) are the portal of entry for pleural fluid into lymphatics; visceral pleural lymphatics do not drain into the pleural space
• Lymphatic reserve capacity is ~30x baseline - a key defense against edema