Hemorrhagic shock renders patients susceptible to the development of acute lung injury in response to a second inflammatory stimulus by as yet unclear mechanisms. We investigated the role of neutrophils (PMN) in alveolar macrophage (AMφ) priming, specifically, the role in mediating Toll-like receptor (TLR)4 and TLR2 cross talk in AMφ. Using a mouse model of hemorrhagic shock followed by intratracheal administration of LPS, we explored a novel function of shock-activated PMN in the mechanism of TLR2 upregulation induced by LPS-TLR4 signaling in AMφ. We showed that antecedent hemorrhagic shock enhanced LPS-induced TLR2 upregulation in AMφ. In neutropenic mice subjected to shock, the LPS-induced TLR2 expression was significantly reduced, and the response was restored upon repletion with PMN obtained from shock-resuscitated mice but not by PMN from sham-operated mice. These findings were recapitulated in mouse AMφ cocultured with PMN. The enhanced TLR2 upregulation in AMφ augmented the expression of macrophage inflammatory protein-2, TNF-α, and macrophage migration inhibitory factor in the AMφ in response to sequential challenges of LPS and peptidoglycan, a prototypical TLR2 ligand, which physiologically associated with amplified AMφ-induced PMN migration into air pouch and lung alveoli. Thus TLR2 expression in AMφ, signaled by TLR4 and regulated by shock-activated PMN, is an important positive-feedback mechanism responsible for shock-primed PMN infiltration into the lung after primary PMN sequestration.
|Journal||American Journal of Physiology - Lung Cellular and Molecular Physiology|
|State||Published - Apr 2006|
- Acute lung injury
- Innate immunity
- Toll-like receptor