Abstract
BackgroundBreakdown of the alveolo-capillary wall is pathognomonic for Acute Lung Injury (ALI). Angiopoietins, vascular-specific growth factors, are linked to endothelial barrier dysfunction, and elevated Angiopoietin-2 (ANG2) levels are associated with poor outcome of ALI patients. Specialized immune cells, referred to as ‘TIE2-expressing monocytes and macrophages’ (TEM), were shown to specifically respond to ANG2 binding. However, their involvement in acute inflammatory processes is so far completely undescribed. Thus, our aim was to assess the dynamics of TEMs in a murine model of ALI.ResultsIntratracheal instillation of LPS induced a robust pulmonary pro-inflammatory response with endothelial barrier dysfunction and significantly enhanced ANG2 expression. The percentage number of TEMs, assessed by FACS analysis, was more than trebled compared to controls, with TEM count in lungs reaching more than 40% of all macrophages. Such distinct dynamic was absent in all other analyzed compartments (alveolar space, spleen, blood). Incubation of the monocytic cell line THP-1 with LPS or TNF-α resulted in a dose-dependent, significant upregulation of TIE2, suggesting that not recruitment from extra-pulmonary compartments but TIE2 upregulation in resident macrophages accounts for increased lung TEM frequencies.ConclusionsFor the first time, our data provide evidence that the activity of TEMs changes at sites of acute inflammation.
Highlights
Breakdown of the alveolo-capillary wall is pathognomonic for Acute Lung Injury (ALI)
Immune cells were gated according to size and granularity defined in the forward (FSC) and side light scatter (SSC) plot
The neutrophil granulocytes were distinguished from macrophages by being CD45+, F4/80−, and Ly6G+ (Gr1 surface expression level)
Summary
Breakdown of the alveolo-capillary wall is pathognomonic for Acute Lung Injury (ALI). Angiopoietins, vascular-specific growth factors, are linked to endothelial barrier dysfunction, and elevated Angiopoietin-2 (ANG2) levels are associated with poor outcome of ALI patients. Specialized immune cells, referred to as ‘TIE2-expressing monocytes and macrophages’ (TEM), were shown to respond to ANG2 binding Their involvement in acute inflammatory processes is so far completely undescribed. Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS) are characterized by an overwhelming host response to severe viral or bacterial infection, aspiration, or severe shock. They lead to heavily increased permeability for proteins and fluids across the alveolo-capillary wall, accompanied by a massive transmigration of leukocytes [1]. Direct interaction of ANG2 with TIE2 is thought to be the primary mechanism [7]
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