Defence Mechanisms of the Lung

Overview

Figure 15.1 - Murray & Nadel: (A) In the absence of PAMPs: tonic suppression of inflammation; DCs carry antigens to lymph nodes → tolerance. (B) In the presence of PAMPs: inflammation initiated; cytokine/chemokine production, PMN recruitment, microbial killing, DC maturation, adaptive immunity activated.

1. Anatomic and Structural Barriers

2. Mucociliary Clearance (MCC)

Structure of the Airway Surface Liquid (ASL)

• Periciliary liquid (PCL): Low-viscosity aqueous layer in which cilia beat freely. Membrane mucin extensions from cilia tips form "grafted brushes" creating electro-repulsion that lubricates ciliary motion.
• Mucus gel layer: Viscoelastic, sits atop the PCL; traps inhaled particles.

Mechanism of Transport

• Ciliated cells are most numerous in trachea and lobar bronchi, decreasing distally.
• Each cilium performs an asymmetric beat: fast forward power stroke propels mucus, slow backward recovery stroke.
• In dense multiciliated zones, coordinated metachronal waves (sequential, not simultaneous) transport mucus proximally from peripheral air spaces toward the mouth.
• Planar cell polarity - developmentally programmed via Wnt signalling - fixes the proximal-to-distal directional axis; surgical reversal of tracheal segments does not reverse cilia beating direction.

Regulation of Ciliary Beat Frequency

• ATP released into extracellular space activates P2Y2 receptors → mucin secretion + increased cilia beat frequency.
• ATP dephosphorylation → adenosine → A2b receptor → sustained hydration and ciliary potentiation.
• Ca²⁺ increases motility; NO increases beat frequency; oxidative stress depresses motility.
• MCC in healthy subjects clears deposited particles within 24 hours.

Impairment

3. Cough Reflex

• Serves as backup to MCC; activated by mechanical and chemical stimuli on airway mucosa.
• Generates high expiratory flows that clear retained secretions.
• Compromised by postoperative pain, narcotic analgesics (depress hypercapnic/hypoxic drive, eliminate sighs), and altered lung mechanics.

4. Biochemical and Antimicrobial Defences

Airway Surface Liquid (ASL) Antimicrobials

Soluble Pattern Recognition Receptors (PRRs)

5. Innate Cellular Immunity

A. Airway Epithelial Cells

• Tight junctions provide a physical barrier to pathogen entry.
• Express Toll-like receptors (TLRs) and other PRRs that recognise PAMPs.
• Upon PAMP recognition, secrete CXCL8 (IL-8) → neutrophil recruitment.
• Three basic pathogen clearance responses: (1) direct killing by soluble PRR or interferon production + phagocytosis; (2) epithelial cell effector recruitment (e.g., neutrophils via IL-8); (3) DC activation → adaptive immunity.

B. Dendritic Cells (DCs)

• Network throughout airway epithelium; particularly dense in trachea and large airways.
• Continuously sample airway lumen by extending processes through tight junctions.
• Without PAMPs: capture antigens → migrate to regional lymph nodes → present antigens to T cells → tolerance (prevents harmful responses to harmless inhaled antigens).
• With PAMPs: undergo maturation → present antigen to T cells → T-cell activation → adaptive immune response.

C. Alveolar Macrophages

• Primary cellular defence of the alveolus for particles <5 µm that reach alveolar surfaces.
• Express TLRs, scavenger receptors (SRs), Fc receptors, complement receptors.
• Functions: phagocytosis, intracellular killing of microbes, antigen presentation, orchestration of inflammatory response.
• In the absence of PAMPs: tonically suppress alveolar inflammation and adaptive immunity (prevent destructive responses to harmless particles).
• In the presence of PAMPs: initiate inflammation: cytokine/chemokine production → recruit PMNs and monocytes → DC maturation → adaptive immunity.

D. Interstitial Macrophages

• Reside in lung interstitium; distinct from alveolar macrophages.
• Participate in local innate sensing and contribute to tissue homeostasis.

E. Neutrophils (PMNs)

• Not resident in healthy lung; rapidly recruited from blood when alveolar macrophages or epithelial cells detect PAMPs.
• Arrive within hours; primary effectors of acute microbial killing.
• Mechanisms: phagocytosis, respiratory burst (reactive oxygen species), degranulation, neutrophil extracellular traps (NETs).

F. Innate Lymphoid Cells (ILCs)

• Resident innate immune cells that provide rapid cytokine responses.
• Bridge innate and adaptive immunity; grouped as ILC1 (IFN-γ), ILC2 (IL-4/IL-5/IL-13), ILC3 (IL-17/IL-22) based on cytokine profile.
• ILC2s are especially important in type 2 airway inflammation (asthma, helminth infection).

G. Monocytes

• Circulating precursors that are recruited to the lung during infection/inflammation.
• Differentiate into macrophages or DCs in the tissue.

6. Recognition System - PAMPs and PRRs

7. Adaptive Immunity

• DCs matured by PAMPs migrate to regional lymph nodes and activate cognate T cells.
• Secretory IgA is the principal antibody in airway secretions; prevents microbial adherence to mucosa.
• B cells/IgG/IgM contribute in lower airways and alveoli.
• CD4+ T helper cells coordinate macrophage activation (Th1) and antibody responses (Th2).
• CD8+ cytotoxic T cells eliminate virally-infected cells.

8. Physiologic Integration - Tonic Suppression vs. Active Defence

Summary Table: Layered Defence