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Chapter 1: Neuroimmune Consequences of Lung and Airway Injury in Blast Trauma

Ongoing work in progress, August 2025

Introduction

Over the past two decades, more than 400,000 U.S. service members have been diagnosed with traumatic brain injury, many associated with blast exposure during deployments to Iraq and Afghanistan. These figures underscore a persistent burden of blast-related trauma in modern conflicts.

Blast waves do not discriminate. In addition to the central nervous system, they often affect two other highly sensitive and densely innervated systems: the lungs and the inner ear. Each serves as an interface with the external world and is directly wired into brainstem circuits that regulate autonomic state and threat responses.

This chapter focuses on the lungs. While usually framed as a gas-exchange surface or an inflammatory target, the lung is also a sensory structure with dense vagal innervation, resident immune sentinels, and bidirectional signaling to the brainstem. I explore how lung injury from blast overpressure and heat may contribute to longer-term neuroimmune sensitization, even when overt neurologic injury is not obvious.

Why I am writing this

I have spent years mapping lung-innervating sensory neurons, including collaborative efforts identifying TMC3 as a marker of vagal afferents that project to the airways and lung parenchyma, characterizing their specific cellular identities and soluble-factor milieu. That work, utilizing bioinformatics, advanced 3D microscopy, and chemogenetic manipulation of specific lung-innervating neurons, motivates a translational question: can drastic hits like blast trauma to a peripheral sensory–immune interface prime long-lasting neural and immune vulnerability, and can we measure or modulate it?

What this chapter will do

Ground the biology of blast lung injury in anatomy and physiology.
Link barotrauma and thermal inhalation injury to two vagal sensory pathways, a mechanoreceptive Piezo2-dominant pathway and a chemothermal TRP-dominant pathway, that map onto the TMC3-positive populations.
Summarize early cytokine programs after blast lung injury and connect them to nociceptor sensitization and neuroimmune priming.
Highlight galanin as a dominant candidate biomarker of resilience in the lung neuroimmune interface.
Propose biomarker panels you can actually measure, with field-to-hospital-to-follow-up timing.
Outline early-phase intervention ideas with suggested windows of use.
Provide a standalone field biomarker and intervention timeline schematic for medics and clinicians.
Link forward to inner ear and hippocampus chapters.
Keep this as a living document that I will expand with re-analyses of open datasets and new literature.

Section 1. Blast trauma 101 for the lung

Blast physics and exposure context

An explosion releases energy fast enough to generate a high-amplitude pressure wave that radiates from the source. High-order explosives detonate and create a supersonic shock front with extreme peak pressures and temperatures. The resulting blast wave usually includes a positive pressure phase followed by a negative phase, and a high-velocity blast wind that compounds tissue loading. Reflections in enclosed or semi-enclosed spaces amplify the dose, often by large factors, and increase injury severity.

Primary blast lung injury is acute lung injury within about 12 hours of exposure, not explained by secondary or tertiary mechanisms. The lung’s gas–liquid interfaces and thin alveolar–capillary barrier make it especially susceptible. The blast wave causes alveolar overdistension, capillary rupture, hemorrhage, interstitial edema, pneumatoceles, and air emboli. Immediate fatalities often relate to air embolism. Survivors frequently require critical care and mechanical ventilation. Evidence-based disease-specific therapeutics are limited, so management is largely supportive and ventilation-strategy driven.

Autonomic and vagal features of PBLI

A stereotyped early vago-vagal reflex response can include brief apnea, bradycardia, and hypotension within seconds, followed by rapid shallow breathing. Animal work shows this response is abolished by vagotomy, highlighting the sensory origin of the reflex cascade and its potential contribution to early mortality and systems-level dysregulation.

Thermal inhalation injury

Superheated gases and toxic combustion products damage airway epithelium, increase permeability, and trigger strong cytokine responses that amplify tissue damage. Firefighting and urban blast scenarios often combine overpressure with thermal injury, so pressure plus heat is the realistic exposure to consider.

Experimental models

Controlled blast tubes, shock tubes, and combined blast-and-burn paradigms reproduce many of these features, including early cytokine surges and leukocyte trafficking.

Takeaway: Real-world blasts rarely deliver a single insult. Overpressure and heat arrive together and interact biologically.

Section 2. Why the lungs matter in a neuroimmune framing

The lungs serve three overlapping roles:

Mechanical interface for gas exchange across an enormous surface area.
Immune barrier that continuously samples the outside world, with rich networks of alveolar and interstitial macrophages, dendritic cells, and tissue lymphocytes.
Sensory organ densely innervated by vagal afferents whose soma reside largely in the nodose ganglion. These detect stretch, chemical irritants, heat, and inflammatory cues, then relay to the nucleus tractus solitarius to guide reflexes and autonomic state.

Mechanically, Piezo2 is a principal mechanotransducer in airway-related sensory neurons and is essential for mechanosensation across multiple systems. Genetic and physiological studies demonstrate Piezo2-dependent respiratory mechanosensation and reflex control in mammals.

Chemothermally, TRPV1 and TRPA1 populate vagal C-fibers and respond to heat, acid, and electrophilic irritants. They are heavily modulated by cytokines released during injury and infection.

TMC3 as the anchor

We identified TMC3-positive vagal lung afferents that split into two broad identities. One is Piezo2-rich mechanosensory and enriched for neuromodulators such as GAL, NPY, PACAP, VIP, NMB, NPPB, and APLN. The other is TRPV1-high chemothermal nociceptive, enriched for inflammatory and neuropeptide signaling partners. A combined overpressure plus heat exposure will stimulate both.

Section 3. Mechanisms that couple injury to altered sensory gain

3a. Barotrauma tunes Piezo2-dependent mechanosensitivity

Inflammatory mediators sensitize Piezo2. Bradykinin and other cytokines rapidly enhance Piezo currents through Gq-biased kinase cascades.
Membrane lipids and PIP2 stabilize Piezo2 function. Depleting PIP2 or altering bilayer tension changes activation thresholds and kinetics.
Cytoskeletal and cadherin tethers modulate force transfer to Piezo channels. Edema, ECM remodeling, and junctional disruption after injury all affect this axis.
In vivo, Piezo2 is required for airway mechanoreflexes including the inflation reflex.

H1. Mechanoreceptive tuning after blast: TMC3⁺ Piezo2⁺ vagal afferents are prime targets of barotrauma. Piezo2 currents are sensitized by G-protein signaling through PKA/PKC, and are modulated by membrane lipids and cytoskeletal context. Post-injury ECM stiffening and inflammatory kinase cascades could shift Piezo2 gating so that stretch and airflow become hyper-salient even when the local peptide milieu (GAL, PACAP, NPY, BDNF) is typically resilience-leaning.

3b. Heat and cytokines potentiate the TRP nociceptor arm

TNF-α enhances TRPV1 excitability and contributes to cough-relevant neural sensitization.
IL-6 increases nociceptor excitability and lowers activation thresholds.
IL-17A from Th17 cells sensitizes nociceptors and maintains inflammatory tone.
Th17 differentiation is driven by IL-6 and TGF-β and stabilized by IL-23.

H2. Chemothermal priming after blast heat/inhalation injury: TMC3⁺ TRPV1⁺ vagal afferents are directly potentiated by cytokines that rise in blast lung injury. IL-6, TNF-α and IL-1β increase TRPV1 expression or sensitivity and drive cough hypersensitivity and nociceptor excitability. TH17 signals can further enhance nociceptor firing via IL-17RA. This matches chronic cough and pain phenotypes reported after airway inflammation and injury.

3c. Lung–brain axis and immune reflexes

Vagal afferents from the lung synapse in the nucleus tractus solitarius and feed into circuits that control breathing and autonomic output. Efferent vagal activity can dampen cytokine production through the cholinergic anti-inflammatory pathway via α7 nicotinic receptors. Blast-induced sensory imbalance can alter both perception and systemic inflammatory set-points.

Section 4. What the omics and biomarker literature says

Single-cell and proteomic profiling of blast lung injury report early myeloid activation with downstream Th17 signatures.
Comparative transcriptomics across species highlight shared damage-response programs and cytokine modules in blast models.
Bulk RNA-seq after combined blast and burn in rats shows early increases in IL-6, TNF-α, CCL2/MCP-1, and CXCL1 at about 48 hours, well positioned to sensitize nociceptors and recruit myeloid cells.
Targeted biomarker panels in rodent and translational studies repeatedly flag IL-6, IL-1β, TNF-α, neutrophil-linked chemokines, and oxidative stress pathways as early drivers.

Neuroactive implications

IL-6, TNF-α, IL-1β prime nociceptor excitability and TRPV1 signaling and can support central sensitization.
CCL2/MCP-1 recruits CCR2+ monocytes near nerve endings, enabling perineural inflammation and indirect neuronal sensitization.
CXCL1 engages CXCR2 pathways and supports neutrophilic protease and ROS milieus that alter mechanotransduction microenvironments.
Th17 axis follows the canonical IL-6 + TGF-β induction, IL-23 stabilization, and IL-17A–mediated nociceptor priming and sustained inflammation.

TMC3 soluble-factor map

TMC3-lineage neurons co-express or secrete neuromodulators GAL, NPY, PACAP, VIP, NMB, NPPB, APLN, and chromogranins. Several of these influence macrophage polarization, epithelial–immune tone, and may buffer against hyperinflammation. This suggests a measurable push–pull between pro-sensitizing cytokines and resilience-leaning neuropeptides in the injured lung.

Section 5. Galanin as a dominant biomarker of resilience

Why galanin

In the TMC3 mechanoreceptive arm, GAL is prominent together with NPY and PACAP. Galanin reduces excitatory transmission, tempers cytokine release in various contexts, and promotes resolution phenotypes in macrophages and epithelial–neuroimmune units. It is a candidate biomarker for neural resilience and anti-inflammatory tone after blast injury.

Where and how to measure

BALF when available in clinical care
Serum or plasma for systemic spillover profiles
Exhaled breath condensate as an exploratory research matrix

Assay feasibility

Commercial ELISAs for GAL exist. Portable lateral-flow immunoassays for galanin are not yet widespread but are feasible with standard antibody pair chemistry. A point-of-care GAL strip could support tracking of neuroimmune resilience tone in blast-exposed cohorts and complement cytokine-based diagnostics.

Section 6. Biomarker panels you can actually measure

Use case: triage and follow-up in combined overpressure plus heat exposure

0–6 hours (field or forward-care)

Vitals and physiology: pulse oximetry, capnography, respiratory rate, brief HRV if available
Portable LFAs: IL-6, CRP, possibly TNF-α
Blood draw: bank serum/plasma for lab cytokine panels
Notes: BAL not feasible in field settings; defer cough sensitivity testing to later windows

48–72 hours (early hospital care)

BALF if clinically indicated; otherwise serum/plasma
Core cytokine panel: IL-6, TNF-α, IL-1β, CCL2/MCP-1, CXCL1, IL-23, IL-17A
Neuropeptide panel: GAL, NPY, PACAP, VIP, NMB, NPPB, APLN
Physiology: capsaicin cough threshold, spirometry, HRV, imaging
Interpretation: high cytokine to neuropeptide ratio suggests primed neuroimmune state; low GAL may indicate diminished resilience tone

1–4 weeks (subacute follow-up)

Repeat serum cytokine and neuropeptide panels
Reassess cough sensitivity, HRV
Optional: psychophysiology screens for panic or autonomic instability

3–6 months and beyond (longitudinal monitoring)

Semiannual serum panels with GAL
Functional endpoints: cough diaries, exercise tolerance, wearable respiratory and HRV metrics

Section 7. Early-phase intervention ideas to evaluate

These are hypothesis-driven concepts for preclinical or early-phase translational research:

Field: antioxidants, resveratrol, vagus nerve stimulation (VNS)
Hospital (24–72 h): IL-6 receptor blockade, TNF inhibitors
Subacute window: IL-17/23 targeting, complement inhibition, macrophage vesicle therapy, continued VNS

Section 8. Standalone schematic (TBD)

A time-windowed field biomarker and intervention timeline schematic for operational use in field and early clinical environments will be developed to visualize these concepts.

Section 9. How this links to the inner ear and hippocampus chapters

Inner ear

Blast and thermal components affect cochlear and vestibular mechanotransduction, impacting spiral ganglia, brainstem relay, and balance pathways. This may contribute to tinnitus, hyperacusis, and disequilibrium.

Hippocampus

Blast exposure primes microglia, perturbs vascular integrity, and increases susceptibility to later psychological or metabolic stressors, contributing to vulnerability in limbic and memory circuits.

Conclusion

Even a single acute blast can plausibly set up long-lived changes in lung sensory gain and immune tone. Barotrauma retunes Piezo2 mechanics, and heat plus cytokines potentiate TRPV1 nociceptors. Early myeloid influx and Th17 axis signaling bridge tissue damage to neural sensitization. Because the lungs are richly innervated and immunologically active, they may act as an upstream priming site that propagates through vagal pathways to influence brainstem and limbic circuits.

The near-term goal is to move from this mechanistic map to practical biomarker panels and time-windowed interventions that reduce chronic suffering in blast-exposed individuals. A medium-term goal is to develop and validate a fieldable galanin assay as a resilience marker and to test the two highlighted hypotheses in translational cohorts.