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Pulmonary ischemia-reperfusion (IR) injury entails acute activation of alveolar macrophages followed by neutrophil sequestration. Although proinflammatory cytokines and chemokines such as TNF-[alpha] and monocyte chemoattractant protein-1 (MCP-1) from macrophages are known to modulate acute IR injury, the contribution of alveolar epithelial cells to IR injury and their intercellular interactions with other cell types such as alveolar macrophages and neutrophils remain unclear. In this study, we tested the hypothesis that following IR, alveolar macrophage-produced TNF-[alpha] further induces alveolar epithelial cells to produce key chemokines that could then contribute to subsequent lung injury through the recruitment of neutrophils. Cultured RAW264.7 macrophages and MLE-12 alveolar epithelial cells were subjected to acute hypoxiareoxygenation (H/R) as an in vitro model of pulmonary IR. H/R (3 h/1 h) significantly induced KC, MCP-1, macrophage inflammatory protein-2 (MIP-2), RANTES, and IL-6 (but not TNF-[alpha]) by MLE- 12 cells, whereas H/R induced TNF-[alpha], MCP-1, RANTES, MIP-1[alpha], and MIP-2 (but not KC) by RAW264.7 cells. These results were confirmed using primary routine alveolar macrophages and primary alveolar type II cells. Importantly, using macrophage and epithelial coculture methods, the specific production of TNF-[alpha] by H/R-exposed RAW264.7 cells significantly induced proinflammatory cytokine/chemokine expression (KC, MCP-1, MIP-2, RANTES, and IL-6) by MLE-12 cells. Collectively, these results demonstrate that alveolar type II cells, in conjunction with alveolar macrophage-produced TNF-[alpha], contribute to the initiation of acute pulmonary IR injury via a proinflammatory cascade. The release of key chemokines, such as KC and MIP-2, by activated type II cells may thus significantly contribute to neutrophil sequestration during IR injury. cytokines; chemokines doi:10.1152/ajplung.00470.2006

In patients requiring mechanical ventilation for acute lung injury or acute respiratory distress syndrome (ARDS), tidal volume reduction decreases mortality, but the mechanisms of the protective effect have not been tully explored. To test the hypothesis that alveolar macrophage activation is an early and critical event in the initiation of ventilator-induced lung injury (VILI), rats were ventilated with high tidal volume (H[V.sup.T]) for 10 min to 4 h. Alveolar macrophage counts in bronchoalveolar lavage (BAL) fluid decreased 45% by 20 min of H[V.sub.T] (P < 0.05) consistent with activation-associated adhesion. Depletion of alveolar macrophages in vivo with liposomal clodronate significantly decreased permeability and pulmonary edema following 4 h of H[V.sub.t] (P < 0.05). BAL fluid from rats exposed to 20 min of H[V.sub.t] increased nitric oxide synthase activity nearly threefold in naive primary alveolar macrophages (P < 0.05) indicating that soluble factors present in the air spaces contribute to macrophage activation in VILI. Media from cocultures of alveolar epithelial cell monolayers and alveolar macrophages exposed to 30 rain of stretch in vitro also significantly increased nitrite production in naive macrophages (P < 0.05), but media from stretched alveolar epithelial cells or primary alveolar macrophages alone did not, suggesting alveolar epithelial cell-macrophage interaction was required for the subsequent macrophage activation observed. These data demonstrate that injurious mechanical ventilation rapidly activates alveolar macrophages and that alveolar macrophages play an important role in the initial pathogenesis of VILI. alveolar epithelial barrier function; ventilator-associated lung injury; acute lung injury; acute respiratory distress syndrome

Byline: Torbjorn S. Haugen (1), Britt Nakstad (1), Torstein Lyberg (1) Abstract: We have studied the expression of tissue factor (TF) and fibrinopeptide A (FPA) generation as well as the release capacity of TNF-[alpha], IL-1[beta], and IL-6 in density-defined subpopulations of alveolar macrophages (AM) and monocytes (Mo). TF was equally expressed on all AM subpopulations and Mo, while the FPA-forming capacity was at the same level in low density AM as in Mo and was significantly (P &lt 0.05) higher in low density AM than in high density AM. The lipopolysaccharide (LPS)-induced release of TNF-[alpha] was higher (P &lt 0.05) in high density AM than in low density AM and in Mo. IL-1[beta] release was undetectable in unstimulated AM and in LPS-stimulated low density AM, while the LPS-induced IL-1[beta] release in high density AM was low compared to the levels demonstrated in Mo. LPS-stimulated IL-6 release was not distinctively different in the AM subpopulations and Mo. The presented study showed that FPA generation and LPS-stimulated TNF-[alpha] release were dependent on the density (i.e., maturity) of AM. This implies that a skewed distribution of AM subpopulations induced by disease processes may profoundly influence the inflammatory reactions, including extravascular activation of coagulation. Author Affiliation: (1) Research Forum, Ullevaal University Hospital, Oslo, Norway Article History: Registration Date: 14/10/2004

Surfactant protein A (SP-A) induces the release of reactive oxygen species upon binding to alveolar macrophages (AM) through a specific surface receptor with high affinity. A multivalent interaction of SP-A with macrophages elicits this functional response from AM, which can be detected using enhanced chemiluminescence. The release of oxygen radicals from AM is possible only when SP-A is attached to zymosan or the surface of the reaction vial.