Macrophage-specific therapy blocks the lung's mechanosensitive immune response to alveolar distension

The lung's mechanosensitive immune response to alveolar overdistension impedes ventilation therapy for hypoxemic respiratory failure. Though mechanistically unclear, the prevailing hypothesis is that the immune response results when alveolar overdistension stretches alveolar macrophages (AMs). Since this hypothesis is untested in live lungs, we optically imaged live mouse alveoli to detect alveolus-adherent, sessile AMs that communicate with the alveolar epithelium through connexin 43-containing (Cx43-containing) gap junctions. Alveolar hyperinflation did not stretch the AMs, but it increased AM Ca2+. AM-specific Cx43 deletion blocked the Ca2+ response, as well as lung injury due to mechanical ventilation at high tidal volume (HTV). HTV-induced injury was also inhibited by AM-targeted delivery of liposomes containing the inhibitor of endosomal Ca2+ release, xestospongin C. We conclude Cx43- and Ca2+-dependent AM-epithelium interactions determine the lung's mechanosensitive immunity, providing a basis for therapy for ventilator-induced lung injury.