Non-Respiratory Functions of the Lungs

West's Respiratory Physiology: The Essentials, 10th Edition

Non-Respiratory Functions of the Lung (per West)

1. Filtration of Blood

• The lung acts as a filter for the venous blood, trapping small thrombi, fat emboli, and aggregates of cells before they can reach the systemic (arterial) circulation, especially the brain.
• This is mentioned under "Defence Mechanisms" in West.

2. Metabolic Functions (the lung as a metabolic organ)

3. Reservoir for Blood

• The pulmonary circulation serves as a blood reservoir for the left ventricle. The lungs hold approximately 450-500 mL of blood at any time.
• During periods of increased left ventricular demand (e.g., exercise), this reservoir can be recruited.

4. Defense Against Inhaled Particles and Microorganisms

• Mucociliary escalator - mucus and cilia trap and remove particles.
• Alveolar macrophages - phagocytose particles, bacteria, and cellular debris.
• Immunoglobulins (IgA, IgG) - secreted in airway fluid.
• Surfactant proteins (SP-A, SP-D) act as opsonins.

5. Synthesis and Secretion of Surfactant

• Type II pneumocytes synthesize surfactant (predominantly dipalmitoylphosphatidylcholine, DPPC), which reduces surface tension and prevents alveolar collapse at end-expiration.

6. Handling of Drugs and Foreign Substances

• The lung can accumulate basic lipophilic amines (e.g., chlorpromazine, imipramine, propranolol).
• Some drugs (e.g., amiodarone) concentrate in lung tissue.

7. Control of Coagulation

• Pulmonary endothelium produces prostacyclin (PGI2) - an inhibitor of platelet aggregation and a vasodilator.
• Also produces thromboxane A2 and plays a role in fibrinolysis.

8. Voice Production

• The lung provides the airflow required for phonation (voice production by the larynx and vocal cords).

Important Note on Source Availability

• Non-respiratory functions / metabolic functions: pp. 182-184 (Chapter 9)
• In some older editions (9th ed.), this appears around pp. 176-178

Nonrespiratory Functions of the Pulmonary Circulation

Overview (p. 160)

"Although the primary purpose of the pulmonary circulation is gas exchange, it has other functions, such as metabolism. The vast vascular surface area of the lungs and the fact that they receive the entire cardiac output, make them uniquely suited to metabolize and modify blood-borne compounds. Compounds can be either activated or inactivated within the pulmonary circulation."

1. Activation of Substances (p. 160)

• The relatively inactive polypeptide angiotensin I is converted to the potent vasoconstrictor angiotensin II by angiotensin-converting enzyme (ACE), located in caveolae on the surface of pulmonary capillary endothelial cells.
• Angiotensin II can then be converted to the vasodilator angiotensin 1-7 (Ang 1-7) by ACE2, which is abundantly expressed in the lungs.
• Notably, ACE2 is the receptor for SARS-CoV-2 - binding of the virus to ACE2 reduces its expression, leading to reduced Ang 1-7 production, increased ROS, vasoconstriction, vascular leakage, and lung injury in COVID-19.

2. Inactivation of Substances (p. 160)

3. Synthesis and Release Under Pathologic Conditions (p. 161)

• Several vasoactive substances are synthesized or stored in the lung but released into the circulation under pathologic conditions.
• In anaphylaxis or an asthmatic attack: histamine, bradykinin, prostaglandins, and leukotrienes are discharged into the circulation.
• Other triggering conditions: pulmonary embolism and alveolar hypoxia.

4. Role in Blood Clotting (p. 161)

• The lung plays a role in blood clotting under normal and abnormal conditions.
• Large numbers of mast cells containing heparin are present in the interstitium, participating in health and disease.

5. Filter Function (p. 161)

• The pulmonary circulation acts as a filter for blood - small intravascular thrombi are removed from the circulation before they can reach the brain or other vital organs.
• This is partly due to high fibrinolytic activity in the endothelial cells of pulmonary arteries (compared with systemic vessels).
• Pulmonary arteriovenous malformations bypass this filter, leading to paradoxical septic or nonseptic embolization - particularly cerebral abscesses or stroke.

6. Neutrophil Reservoir and Host Defense (p. 161)

• Pulmonary capillaries sequester a higher concentration of neutrophils than most other organs.
• These neutrophils are readily recruitable as host defense agents.
• About 70% of migrating neutrophils leave pulmonary capillaries at tricellular corners (where margins of three endothelial cells converge).

Role of the Lung in Blood Clotting

Fishman's Pulmonary Diseases and Disorders, 2-Volume Set

1. Weibel-Palade Bodies and Hemostasis (p. 60)

• Tissue-type plasminogen activator (t-PA) - a major fibrinolytic agent
• Endothelin-1
• P-selectin (leukocyte adhesion receptor)
• Interleukin-8
• CD63/LAMP-3 (tetraspanin)
• Rab27a (small GTPase)

"Thus, Weibel–Palade bodies are actively involved in hemostasis as well as in vasoactive and inflammatory responses."

• Fishman's, p. 60

2. Nonrespiratory Metabolic Functions via Caveolae (p. 60)

"Many of the nonrespiratory metabolic functions of the lung - particularly the transformation of certain bioactive substances, such as angiotensin and prostaglandins - are performed in endothelial cells. Caveolae (or plasmalemmal vesicles) have been implicated in these processes."

3. Coagulation-Fibrosis Axis in the Lung (p. 411)

• Factor Xa and thrombin activate lung fibroblasts via PAR-1 (proteinase-activated receptor-1), promoting fibroblast proliferation and differentiation into myofibroblasts.
• Thrombin upregulates PAI-1 (plasminogen activator inhibitor-1), resulting in increased fibrin matrix - which inhibits surfactant and leads to alveolar collapse.
• Lysophosphatidic acid (LPA), a platelet-derived molecule during coagulation, promotes pulmonary fibrosis via TGF-β1 activation.
• Endothelin-1 (ET-1), an activator of the extrinsic coagulation cascade, exerts profibrotic effects on lung fibroblasts.

Summary Table

Immunologic Functions of the Lung

Fishman's Pulmonary Diseases and Disorders, 2-Volume Set

Overview

"The lung is a vast organ comprised of conducting airways, alveoli, and tissue parenchyma that is highly specialized to sample the diverse antigens that we breathe in. The lung is equipped with a well-orchestrated immune system to clear particulate debris and to eliminate inhaled pathogens and toxins to protect the delicate capillary-alveolus barrier system that is critical for gas exchange. The immune system in the lung has evolved complex and diverse innate and adaptive immune responses to accomplish these critical functions of lung homeostasis and host defense."

• Fishman's, p. 303

A. INNATE IMMUNE FUNCTIONS

1. Neutrophils (p. 299)

• Lungs act as a reservoir of neutrophils under steady state - with infection or injury, they are promptly activated and recruited to the alveolar compartment and airways.
• Among the first phagocytes recruited in acute lung disease.
• Functions: generate free radicals, release neutrophil elastases and proteases, phagocytosis and degradation of invading microbes.
• Can be primed by IL-8, GM-CSF, platelet activating factor, and ROS - extending life span, upregulating CD11b, and optimizing NADPH oxidase assembly.
• In chronic lung disease, persistently recruited neutrophils can cause significant tissue damage when granule contents are released in an uncontrolled manner.

2. Innate Lymphoid Cells / ILCs (p. 299)

3. Alveolar Macrophages (AMs) (pp. 309-310)

• Direct microbicidal activity - phagocytosis and phagolysosomal killing of pathogens (primary role).
• Cytokine release - TNF-α, IL-1α, IL-1β, IL-6, and chemokines that recruit and activate monocyte-derived macrophages, neutrophils, and lymphocytes.
• Resolution and repair - efferocytosis (phagocytosis of apoptotic neutrophils and injured cells); produce anti-inflammatory mediators (IL-10, TGF-β) and pro-resolving lipid mediators (resolvins, protectins, maresins).
• Phenotypic flexibility: M1 ("classically activated" by IFN-γ/LPS - microbicidal, produce TNF-α, IL-6, ROS) vs. M2 ("alternatively activated" by IL-4/IL-13 - express arginase 1, chitinase-like proteins, CD206).

4. T Cell Subsets with Innate Properties (p. 303)

• NKT cells - express both αβ TCR and NK cell markers; recognize glycolipid antigens via CD1d; produce diverse cytokines in mucosal lung immunity; only 0.1-0.2% of circulating lymphocytes.
• γδ T cells - enriched at mucosal/epithelial surfaces including respiratory tract; represent 8-20% of resident pulmonary lymphocytes; maintain normal airway responsiveness, provide protective immunity, and support tissue healing and epithelial maintenance.
• MAIT cells - activated by microbial riboflavin metabolite-derived antigens via MR1; secrete TNF-α, IFN-γ, and IL-17 against microbial pathogens; promote monocyte differentiation into dendritic cells, bridging innate to adaptive immunity.

B. ADAPTIVE IMMUNE FUNCTIONS

5. Overview of Adaptive Immunity in the Lung (pp. 300-301)

• A range of pathogens (viruses, bacteria)
• Environmental inhalants (cigarette smoke, dusts)
• Allergens

6. Generation of an Immune Response (pp. 301-302)

• Antigens encountered in the mucosal surfaces, lung, and airway mucosa are transported to draining mediastinal lymph nodes.
• Dendritic cells (DCs) and macrophages (APCs) present antigen to naïve T and B lymphocytes, which leads to activation, proliferation, and differentiation into effector cells.
• Three signals for T cell activation:
  • Signal 1: TCR ligation to MHC/peptide complex on APC
  • Signal 2: CD28 on T cell binds CD80/CD86 on APC (co-stimulation; without this, T cells become anergic)
  • Signal 3: Polarizing cytokine signals from innate cells and local tissue microenvironment
• Memory T cells persist long-term and provide a faster, more vigorous response on re-exposure.

7. T Helper Cell Differentiation (pp. 301-302, Fig. 19-4)

8. Humoral vs. Cell-Mediated Immunity (p. 300)

• Humoral immunity: Mediated by B lymphocytes producing antibodies in response to antigens (e.g., secretory IgA in airways, IgG in alveoli).
• Cell-mediated immunity: Involves T lymphocytes, cytotoxic T cells (CD8+ - destroy virus-infected cells, tumor cells), activated macrophages, and NK cells.

9. Hypersensitivity Reactions in the Lung (p. 303)

• Type 1 (IgE/Th2): Asthma, allergic lung disease
• Type 2 & 3: Autoimmune antibody-mediated lung diseases
• Type 4 (delayed-type hypersensitivity): Chronic Th1-driven macrophage and lymphocyte activation (e.g., hypersensitivity pneumonitis, sarcoidosis)

Acid-Base Balance

Fishman's Pulmonary Diseases and Disorders, 2-Volume Set

I. INTRODUCTION (p. ~269)

• Lungs are responsible for modulating arterial PCO₂
• Kidneys are primarily responsible for modulating plasma [HCO₃⁻]

II. BASIC PHYSIOLOGY OF THE KIDNEY IN ACID-BASE BALANCE (pp. ~269-270)

• Normal metabolism generates 15,000 mmol of CO₂ daily (volatile acid) - excreted by the lungs.
• Also generates nonvolatile ("fixed") acid at 1 mEq/kg/day - primarily from oxidation of sulfur-containing proteins → sulfuric acid.
• The kidneys must excrete 50-100 mEq of nonvolatile acid daily to prevent metabolic acidosis.
• Before renal excretion, acid is initially buffered by:
  • Bicarbonate buffer (primary extracellular)
  • Non-bicarbonate buffers (Buf⁻) - primarily hemoglobin and proteins (intracellular)

Renal Mechanisms for Acid Excretion:

1. HCO₃⁻ reabsorption - >99% of filtered bicarbonate is reabsorbed, mostly in the proximal tubule via Na+/H+ exchange, powered by Na+/K+ ATPase.
2. Titratable acid excretion - H+ is secreted into tubular lumen and combines with phosphate (HPO₄²⁻ → H₂PO₄⁻). Limited by availability of urinary buffers.
3. Ammonium (NH₄⁺) excretion - most important mechanism for net acid excretion. Glutamine is metabolized in proximal tubule → NH₃ + HCO₃⁻. NH₃ diffuses into tubular lumen, combines with H⁺ → NH₄⁺, which is trapped and excreted. NH₃ production is regulated by:
   • Plasma potassium (hyperkalemia → intracellular alkalosis → ↓NH₃ synthesis)
   • Urinary pH (inability to acidify urine → ↓NH₄⁺ trapping → ↓net acid excretion)

III. RESPIRATORY CONTRIBUTION TO ACID-BASE BALANCE (p. 270)

CO₂ Transport in Blood:

1. Dissolved CO₂ (limited by solubility coefficient: 0.03 mM/mmHg)
2. Carbamino compounds (CO₂ + amino groups of proteins)
3. Bicarbonate (majority) - within red blood cells via carbonic anhydrase:

   CO₂ + H₂O → H₂CO₃ → H⁺ + HCO₃⁻

   • H⁺ is buffered by hemoglobin (with increased affinity at low PO₂ in peripheral capillaries)
   • HCO₃⁻ leaves the RBC in exchange for Cl⁻ (chloride shift)

In the Pulmonary Circulation:

• Enhanced oxygenation of hemoglobin → release of bound H⁺
• H⁺ + HCO₃⁻ → (via carbonic anhydrase) → CO₂
• CO₂ passively diffuses from blood into pulmonary interstitium → alveolar space → expired

Chemoreceptor Control of Ventilation:

IV. ACUTE AND CHRONIC ADAPTATION TO RESPIRATORY ACIDOSIS (pp. 270-271)

Acute Respiratory Acidosis:

• ↑PCO₂ → ↓pH
• Buffering (not renal compensation): H⁺ buffered by hemoglobin and intracellular non-bicarbonate buffers
• Expected change: for every ↑10 mmHg PCO₂, HCO₃⁻ rises by only ~1 mEq/L (acute buffering only)
• pH change: for every ↑10 mmHg PCO₂, pH falls ~0.08 units

Chronic Respiratory Acidosis:

• Renal compensation kicks in over 3-5 days:
  • ↑ ammonium excretion
  • ↑ HCO₃⁻ reabsorption and regeneration
• For every ↑10 mmHg PCO₂ (chronic), HCO₃⁻ rises by ~3.5 mEq/L
• pH is largely (but not completely) corrected

V. RENAL ADAPTATION TO RESPIRATORY ALKALOSIS (pp. 271-272)

Acute:

• ↓PCO₂ → ↑pH
• Buffering: HCO₃⁻ enters cells in exchange for H⁺ (H⁺ released from intracellular buffers)
• For every ↓10 mmHg PCO₂ (acute), HCO₃⁻ falls by ~2 mEq/L

Chronic:

• Renal compensation: ↓ HCO₃⁻ reabsorption, ↓ ammonium excretion
• For every ↓10 mmHg PCO₂ (chronic), HCO₃⁻ falls by ~5 mEq/L

VI. RESPIRATORY ADJUSTMENT TO METABOLIC ACIDOSIS (p. 272)

• The respiratory system provides rapid compensation (within minutes to hours).
• ↓HCO₃⁻ → chemoreceptor stimulation → hyperventilation → ↓PCO₂
• Winter's formula predicts expected PCO₂:

  Expected PCO₂ = 1.5 × [HCO₃⁻] + 8 ± 2 mmHg

• If actual PCO₂ is higher than predicted → coexisting respiratory acidosis
• If actual PCO₂ is lower than predicted → coexisting respiratory alkalosis

VII. RESPIRATORY ADJUSTMENT TO METABOLIC ALKALOSIS (p. 272)

• ↑HCO₃⁻ → suppression of chemoreceptors → hypoventilation → ↑PCO₂
• However, hypoxia from hypoventilation eventually limits the compensatory response (peripheral chemoreceptors stimulate breathing when PaO₂ falls).
• PCO₂ rarely exceeds 55-60 mmHg as compensation for metabolic alkalosis.
• Expected PCO₂ = 0.7 × [HCO₃⁻] + 21 ± 2 mmHg

VIII. ALTERNATIVE CONCEPTS OF ACID-BASE BALANCE (p. 272)

• Proposes that pH is determined by three independent variables:
  • PCO₂
  • Total weak acid concentration (mainly albumin and phosphate)
  • Strong Ion Difference (SID) = [Na⁺ + K⁺ + Ca²⁺ + Mg²⁺] - [Cl⁻ + lactate⁻]
• A decrease in SID → acidosis; increase → alkalosis
• Fishman's assessment: Traditional bicarbonate/anion gap approach remains clinically most useful - studies comparing Stewart's method vs. traditional approach show only marginal differences; correcting AG for hypoalbuminemia is equally effective.
• A temperature-based concept: inverse relationship between pH and body temperature across species - used in temperature correction during hypothermia (both pH-stat and alpha-stat strategies).

IX. CLINICAL APPROACH TO ACID-BASE DISORDERS (pp. 272-278)

Step 1: Base Excess / Base Deficit Notation (p. 273)

• Useful in the operating room for acute intraoperative changes
• Not reliable in chronic respiratory disorders (may falsely suggest "base deficit" when low HCO₃⁻ is actually appropriate compensation)

Step 2: Use of Nomograms (p. 273, Fig. 17-4)

• Plot pH, PCO₂, and HCO₃⁻ on the acid-base confidence band nomogram
• Values falling within a confidence band = simple disorder
• Values falling outside the band = mixed disorder

Step 3: Anion Gap (AG)

AG = Na⁺ - (Cl⁻ + HCO₃⁻); normal = 12 ± 2 mEq/L

• Elevated AG metabolic acidosis: increased acid production (see Table 17-2)
• Normal AG (hyperchloremic) metabolic acidosis: loss of HCO₃⁻ or failure to excrete acid
• Correct AG for hypoalbuminemia: AG + 2.5 × (4 - [albumin g/dL])

X. CLINICAL CASE ILLUSTRATIONS (pp. 277-280)

Case 1: Metabolic Acidosis (p. 277)

Case 2: Metabolic Alkalosis

• GI hydrogen loss (gastric suction/vomiting)
• Renal hydrogen loss (mineralocorticoid excess, loop/thiazide diuretics)
• Posthypercapnic alkalosis
• Intracellular H⁺ shift (hypokalemia)
• Alkali administration
• Contraction alkalosis