LSC Abstract – Differentiation between inflammation and hyperinflammation in the murine lung

The lung is perennially challenged by inflammatory stimuli. We hypothesize that pulmonary inflammation follows a modular concept, in which the mediator profile determines whether inflammation remains salutary or escalates into organ dysfunction. Some mediators are liberated whenever pulmonary inflammation is induced, whereas others emerge during severe inflammation – which we term hyperinflammation. The current study was designed to identify mediators that drive inflammation into hyperinflammation. C57/BL6 mice were instilled with 50µL HCl pH=2.0 or 0.9% NaCl and ventilated at V T =16mL/kg, f=90min -1 , PEEP=2cmH 2 O and FiO 2 =0.3. After 1h, IL-6+CXCL1, TNF+CXCL10 or HMGB1 were aerosolized into the lungs, which were ventilated for further 6h. In a second approach, lungs were injured with HCl pH=1.5 followed by instillation of an anti-HMGB1 antibody and 5h of ventilation. Lung mechanics, oxygenation, inflammation and oedema formation were analysed. In addition, precision-cut lung slices (PCLS) were prepared from murine and human lungs to study acid-induced tissue damage. Acid pH=2.0 and NaCl induced mild inflammation without loss of lung function, whereas HCl pH=1.5 caused acute lung injury. Instillation of IL-6+CXCL1 had no injurious effect. In contrast, TNF+CXCL10 deteriorated lung functions in acid pre-treated lungs and HMGB1 caused injury in all lungs. In PCLS, viability was decreased by acid in a pH-dependent manner and tissue damage was accompanied by release of HMGB1. The anti-HMGB1 antibody provided full protection from acid-induced lung injury. We conclude that CXCL1 and IL-6 contribute to benign inflammation, while TNF, CXCL10 and HMGB1 characterize the deleterious hyperinflammation module.