Two hit induced acute lung injury impairs cognitive function in mice: A potential model to study cross talk between lung and brain.

Acute lung injury (ALI), a pulmonary inflammatory disorder, is associated with high morbidity and mortality rates. Interestingly, ALI survivors have been reported for some neurocognitive deterioration at/after discharge. However, the molecular factors behind such extra pulmonary manifestation are not clearly known. The present work was designed to investigate lung-brain cross talk in experimental mice for deciphering primary molecular factors that may be involved in ALI-mediated cognitive impairment. ALI was induced in Balb/c mice by intra-tracheal administration of either 0.1 N HCl (2 ml/kg) or LPS (1 mg/kg) as single hits or both agents were administered successively to mimic the 'two hit' model. Interestingly two hit-mediated ALI resulted in exaggerated inflammatory response as reflected by increased pulmonary neutrophils and inflammatory factors (TNF-α/IL-1β/IL-6). Additionally, two hits resulted in delayed resolution of lung inflammation and was coupled with persistent decline in memory, as assessed by Morris water maze test. Further, two hits elevate serum levels of TNF-α/IL-1β which was associated with compromised blood brain barrier (BBB), as evident by decreased expression of occludin/claudin-5 and consequent Evans-blue extravasation in hippocampus 1 week post injury. Finally, dexamethasone protects against the two hit mediated cognitive impairment by lowering the pro-inflammatory factors (TNF-α/IL-1β) both in lungs and blood. Overall, we report for the first time that 'two hit' mediated ALI cause persistent cognitive impairment in mice partly via up-regulating systemic expression of TNF-α/IL-1β that may disrupt BBB and hence the model may be a useful tool to examine the lung-brain cross-talk at the molecular level for exploring newer therapeutics.