NETosis

Our immune system is made up of a complex network of cells and molecules that work together to counteract detrimental effects from external pathogens such as viruses, bacteria, parasites, fungi and protozoa, or from the growth of cancer cells. Typically, when a pathogen enters our bodies, it’s entrapped by specific white blood cells, called neutrophils, and is eliminated.

What are neutrophil extracellular traps?

A variety of pathogenic stimuli, such as external pathogens, antibodies and immune complexes, cytokines, microcrystals, or other physiological stimuli can trigger a process called NETosis, the formation of neutrophil extracellular traps (NET). When neutrophils, which represent the most abundant type of white blood cells, are recruited to the site of inflammation, they entrap and eliminate pathogens by expelling NETs into the extracellular environment and eventually undergo spontaneous death.

Under normal circumstances, NETosis is a self-defense strategy. Nonetheless, the formation of NETs can become per se a pathogenic stimulus in many diseases such as cancer, autoimmune diseases (e.g. rheumatoid arthritis), lung diseases, atherosclerosis, venous thromboembolic diseases, and COVID-19.

ARDS is an acute, inflammatory lung injury characterized by increased pulmonary vascular permeability and significant impairments in lung mechanics and gas exchange.

ARDS is a complex, heterogeneous syndrome with a mortality rate that may exceed 40% and the onset of ARDS can be associated with direct or indirect lung injuries, such as Pneumonia, Aspiration, Sepsis or Trauma. In ARDS, acute inflammation generates severe consequences and eventually leads to a chronic dysfunction of multiple mechanisms through massive cytokine secretion by infiltrating neutrophils, resident macrophages, endothelial cells and infiltrating fibroblasts.

IL-8 levels in ARDS patients have been shown to correlate with a poor progression and outcome of the pathology. To date, Reparixin, an inhibitor of IL-8 signaling, is currently at an investigational stage in clinical application, having previously been shown to be safe and effective at multiple levels in preclinical studies. Indeed, in multiple animal models of acute lung injury (induced by infections or pharmacological treatment), Reparixin was able to: inhibit neutrophil infiltration with reduction of NETosis, restore a partial endothelial permeability and to reduce fibrosis, thus ameliorating general lung respiratory function.