Abstract
The mortality rate of patients with critical illness has decreased significantly over the past two decades, but the rate of decline has slowed recently, with organ dysfunction as a major driver of morbidity and mortality. Among patients with the systemic inflammatory response syndrome (SIRS), acute lung injury is a common component with serious morbidity. Previous studies in our laboratory using a murine model of SIRS demonstrated a key role for NADPH oxidase 2 (Nox2)-derived reactive oxygen species in the resolution of inflammation. Nox2-deficient (gp91phox−/y) mice develop profound lung injury secondary to SIRS and fail to resolve inflammation. Alveolar macrophages from gp91phox−/y mice express greater levels of chemotactic and pro-inflammatory factors at baseline providing evidence that Nox2 in alveolar macrophages is critical for homeostasis. Based on the lung pathology with increased thrombosis in gp91phox−/y mice, and the known role of platelets in the inflammatory process, we hypothesized that Nox2 represses platelet activation. In the mouse model, we found that platelet-derived chemokine (C-X-C motif) ligand 4 (CXCL4) and CXCL7 were increased in the bronchoalveolar fluid of gp91phox−/y mice at baseline and 24 h post intraperitoneal zymosan-induced SIRS consistent with platelet activation. Activated platelets interact with leukocytes via P-selectin glycoprotein ligand 1 (PSGL-1). Within 2 h of SIRS induction, alveolar neutrophil PSGL-1 expression was higher in gp91phox−/y mice. Platelet-neutrophil interactions were decreased in the peripheral blood of gp91phox−/y mice consistent with movement of activated platelets to the lung of mice lacking Nox2. Based on the severe lung pathology and the role of platelets in the formation of neutrophil extracellular traps (NETs), we evaluated NET production. In contrast to previous studies demonstrating Nox2-dependent NET formation, staining of lung sections from mice 24 h post zymosan injection revealed a large number of citrullinated histone 3 (H3CIT) and myeloperoxidase positive cells consistent with NET formation in gp91phox−/y mice that was virtually absent in WT mice. In addition, H3CIT protein expression and PAD4 activity were higher in the lung of gp91phox−/y mice post SIRS induction. These results suggest that Nox2 plays a critical role in maintaining homeostasis by regulating platelet activation and NET formation in the lung.
Highlights
Despite numerous technological advances in intensive care in recent years, mortality from sepsis and the systemic inflammatory response syndrome (SIRS) remains static
We sought to unravel the specific mechanisms by which NADPH oxidase 2 (Nox2) might protect the lung, and to characterize the events that result in neutrophilic infiltration in the alveolar space, resulting in severe thrombosis, hemorrhage, and mortality
We recently demonstrated that Nox2 in alveolar macrophages plays a homeostatic role in repressing basal chemokine secretion into the alveolar space [7]
Summary
Despite numerous technological advances in intensive care in recent years, mortality from sepsis and the systemic inflammatory response syndrome (SIRS) remains static. The mortality rate has decreased substantially, more than 25–30% of patients with sepsis will die from complications of multi-organ injury [1]. Among many organ systems at risk during SIRS, acute lung injury and the resultant acute respiratory distress syndrome is a common cause of severe morbidity. Acute respiratory distress syndrome is characterized by acute and diffuse inflammation in the lung with rapid neutrophil infiltration and pulmonary edema. The contribution of neutrophils to the lung injury process is well-recognized with exuberant cell activation and the release of both reactive oxygen species (ROS) and proteolytic granule contents [4]
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