Alveolar Macrophages and Toll-like Receptor 4 Mediate Ventilated Lung Ischemia Reperfusion Injury in Mice

Abstract

Background Ischemia reperfusion (I/R) injury involves sterile inflammation and is commonly associated with diverse clinical situations such as hemorrhage followed by resuscitation, transient embolic events, and organ transplantation. I/R injury can induce lung dysfunction whether the I/R occurs in the lung itself or in a remote organ. Recently, evidence has emerged that receptors and pathways of the innate immune system are involved in recognizing sterile inflammation and overlap considerably with those involved in recognition and response to pathogens. Methods We used a mouse surgical model of transient unilateral left pulmonary artery occlusion without bronchial involvement to create ventilated lung I/R injury. Additionally, we mimicked nutritional I/R injury in vitro by transiently depriving cells of all nutrients. Results Compared with sham-operated mice, mice subjected to ventilated lung I/R injury had upregulated lung expression of inflammatory mediator messenger RNA for IL-1β, IL-6, and CXCL1 and 2, paralleled by histologic evidence of lung neutrophil recruitment, and increased plasma levels of IL-1β, IL-6 and HMGB1 proteins. This inflammatory response to I/R required toll-like receptor-4. Furthermore, we demonstrated in vitro cooperativity and cross-talk between macrophages and endothelial cells, resulting in augmented inflammatory responses to I/R. Remarkably, we found that selective depletion of alveolar macrophages rendered mice resistant to ventilated lung I/R injury. Conclusions Our data reveal that alveolar macrophages and the pattern recognition receptor, toll-like receptor-4 are required for the generation of the early inflammatory response to lung I/R injury.

Akt2 Deficiency Protects from Acute Lung Injury via Alternative Macrophage Activation and miR-146a Induction in Mice

“…Specifically, TLR4 signaling plays a central role in macrophage activation in both septic and aseptic inflammation, including ARDS (32,33,(51)(52)(53)(54)(55), and is critical in the pathogenesis of disease (12,32,55). TLR4 signaling is controlled by MyD88-or TRIF-dependent downstream effectors, the signals of which converge for TRAF6 activation and NF-kB nuclear translocation (56).…”

“…Akt2 depletion induces C/EBPb via negative regulation of the microRNA (miRNA) miR-155, known to target C/EBPb and promote M1 (22,25,31). Additionally, TLR4 signaling was shown to play an important role in alveolar macrophage activation in animal models of ALI (12,32,33). TLR4 signaling is regulated by the antiinflammatory miRNA, miR-146a, which targets and suppresses downstream TLR4 mediators, such as TNFR-associated factor (TRAF)-6, IRAK1, and IRF5 (34,35).…”

Treatment with Recombinant Trichinella spiralis Cathepsin B–like Protein Ameliorates Intestinal Ischemia/Reperfusion Injury in Mice by Promoting a Switch from M1 to M2 Macrophages

“…Macrophages are an essential element in the orchestration and expression of innate immunity and adaptive immune responses. Increasing evidence has proved that macrophages participate actively in I/R injury, and macrophage depletion has been shown to diminish organ damage in models of intestinal I/R injury (8)(9)(10)(11)(12)(13). Moreover, macrophages seem to modulate the recruitment of neutrophils that occurs hours after intestinal I/R injury (12).…”

Lung-Restricted Antibodies Mediate Primary Graft Dysfunction and Prevent Allotolerance after Murine Lung Transplantation

“…This, in turn, can cause phenotypic switch and activation of immune response to other antigens present on the phagocytized membrane, leading to epitope spreading to other sAgs, and likely to alloantigens. The development of PGD and associated inflammatory response can also lead to infiltration of neutrophils and activation of macrophages (37,38). These macrophages have an important role for further induction of autoimmune responses.…”