Lung-brain axis-generated inflammatory biomarkers in traumatic brain injury and acute respiratory distress syndrome: Role of mechanical ventilation/stress

Abstract

Rationale

The unmet need for effective therapeutic strategies to address the bi-directional perturbation of the lung-brain axis following traumatic brain injury (TBI) or associated with Acute Lung Injury/Acute Respiratory Distress Syndrome (ALI/ARDS) is increasingly recognized. Contributing to this unmet need is the absence of reliable biomarkers that reflect the severity of lung-brain axis disruption. We assessed specific potential lung-brain axis biomarkers in TBI and ALI/ARDS subjects and explored the specific influence of exposure to mechanical ventilation.

Methods

Serum biomarker levels from TBI (n = 97) and ARDS subjects (n = 39) and healthy controls (n = 46) were analyzed (MesoScale Discovery ELISA) utilizing a critical illness lung-brain axis biomarker panel (CILBA) that included DAMPS (eNAMPT, S100A8), inflammatory cytokines (IL-6, IL-1β, IL-1RA, TNF-α), vascular biomarkers (PSGL-1, ANG-2), and neurotrauma biomarkers (GFAP or Glial fibrillary acidic protein, NFL or neurofilament light chain, Tau).

Results

TBI and ARDS subjects demonstrated significant elevations in each biomarker (compared to controls) with two exceptions: PSGL-1 was exclusively elevated in ARDS and GFAP exclusively elevated in TBI. Mechanically ventilated subjects exposed exhibited significantly DAMP, vascular and neurotrauma biomarker elevations compared to unexposed subjects. With the exception of GFAP, Ang-2, and S100A8, biomarker elevations were linked to ICU days or mortality.

Conclusions

These results highlight overlapping innate immunity dysregulation as a manifestation of lung-brain axis disruption in both TBI- and ARDS-exposed subjects with amplified dysregulation with mechanical ventilation. Additional longitudinal studies of well-phenotyped TBI and ARDS subjects may substantiate the prognostic value of biomarker analyses in assessing the severity of bidirectional lung-brain axis injuries.