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Updated: Jun 27, 2026
Alveolar Macrophage Phagocytosis and Bacteria Clearance in Mice
Published on: March 2, 2019
Alveolar macrophages from septic mice promote polymorphonuclear leukocyte transendothelial migration via an
Zhanfei Wang1, Tao Rui, Min Yang
1Critical Illness Research, Lawson Health Research Institute, London Health Sciences Centre, London, Ontario, Canada.
Abstract:
Alveolar macrophages (AMphi) have been implicated in the polymorphonuclear leukocyte (PMN) recruitment to the lungs during sepsis. Using an in vivo murine model of sepsis (feces in the peritoneum), we show that peritonitis leads to increased activation of AMphi and PMN migration into pulmonary alveoli. To assess cellular mechanisms, an in vitro construct of the pulmonary vascular-interstitial interface (murine AMphi, pulmonary endothelial cells, and PMN) and a chimera approach were used. Using immunologic (Abs) and genetic blockade (CXCR2-deficient AMphi), we show that CXC chemokines in septic plasma are responsible for the activation of AMphi. The activated AMphi can promote PMN transendothelial migration, even against a concentration gradient of septic plasma, by generating platelet-activating factor and H(2)O(2). Platelet-activating factor/H(2)O(2) induce an oxidant stress in the adjacent endothelial cells, an event that appears to be a prerequisite for PMN transendothelial migration, since PMN migration is abrogated across Cu/Zn-superoxide dismutase overexpressing endothelial cells. Using gp91-deficient endothelial cells, we show that NADPH oxidase plays an important role in the AMphi-induced PMN transendothelial migration. Pharmacologic/small interfering RNA blockade of Src kinase inhibits AMphi-induced endothelial NADPH oxidase activation and PMN migration. Collectively, our findings indicate that the PMN transendothelial migration induced by septic AMphi is dependent on the generation of superoxide in endothelial cells via the Src kinase/NADPH oxidase signaling pathway.
Insights
Sepsis activates alveolar macrophages (AMphi), which then recruit neutrophils (PMN) to the lungs. This process involves AMphi generating platelet-activating factor and H2O2, leading to endothelial cell oxidant stress and PMN migration via Src kinase and NADPH oxidase.
Area of Science:
- Immunology
- Cell Biology
- Pulmonary Medicine
Background:
- Alveolar macrophages (AMphi) play a role in neutrophil (PMN) recruitment during sepsis.
- Sepsis-induced peritonitis leads to AMphi activation and PMN migration into lung alveoli.
Purpose of the Study:
- To elucidate the cellular mechanisms underlying AMphi-mediated PMN recruitment to the lungs during sepsis.
- To identify key signaling pathways involved in AMphi-induced PMN transendothelial migration.
Main Methods:
- In vivo murine model of sepsis (peritonitis).
- In vitro pulmonary vascular-interstitial interface model.
- Immunologic and genetic blockade (e.g., CXCR2-deficient AMphi, gp91-deficient endothelial cells).
- Pharmacologic and small interfering RNA (siRNA) blockade of Src kinase.
Main Results:
- Septic plasma CXC chemokines activate AMphi.
- Activated AMphi promote PMN transendothelial migration by generating platelet-activating factor and H2O2.
- Endothelial cell oxidant stress, mediated by NADPH oxidase via Src kinase, is essential for PMN migration.
- PMN migration is abrogated across endothelial cells overexpressing Cu/Zn-superoxide dismutase.
Conclusions:
- Septic AMphi-induced PMN transendothelial migration is dependent on endothelial cell superoxide generation.
- The Src kinase/NADPH oxidase signaling pathway is critical for AMphi-mediated PMN recruitment in sepsis-induced lung inflammation.
