Dompé

Sophie Toya

Acute respiratory distress syndrome is a cause of hypoxemic respiratory failure due to lung injury that may be due to a variety of reasons, including SARS-COV2, as well as many other infectious and non-infectious agents. Although we gained an improved understanding of the syndrome’s pathogenesis over the last few years and during the COVID-19 pandemic, we still do not have effective pharmacologic treatment. However, we do know that neutrophils, the most abundant immune cells in the body, play a significant role through their activation and recruitment in the lungs. Although neutrophils have an armamentarium of responses against invading pathogens, the most important and perhaps the least known ones are NETs or neutrophil extracellular traps.

What are NETs?

They are extracellular structures composed of granules and nuclear and mitochondrial constituents assembled on a scaffold of decondensed chromatin interlaced with antimicrobial proteins and peptides. NETs represent an innate defense mechanism; they physically immobilize and kill invading microorganisms by achieving a high local concentration of antimicrobial agents. However, they can also be injurious to the host as they can cause local cellular injury and promote microthrombosis. In fact, studies both in animal models of acute lung injury (the equivalent of ARDS in animals) and human patients have shown a correlation between NET formation in tissue and disease severity and prognosis.

So, a strategy of moderating NET formation with appropriate antibiotics (upon documentation of infection) and best supportive care would be potentially beneficial for ARDS patients.

But how do we cast our nets on NETs?

First, we need to be able to detect them in patients using noninvasive methods and in real-time to modify the disease course.

Several methods exist, including isolation of neutrophils from peripheral blood, purification, and short-term culture followed by identification of produced NETs through the use of cell-impermeant dyes (i.e., SYTOX Green, Thermo Fisher Scientific), measurement of MPO (myeloperoxidase) or through direct detection of NETs by immunofluorescence microscopy. Alternatively, serum markers of NET production in vivo, such as quantitation of cell-free DNA, MPO-DNA complexes, and citrullinated histone H3, can be used. The problem is that 1) these assays are not widely available at the point of care, and 2) they have no validated threshold for linkage to NETs, meaning they need to be repeated longitudinally to detect changes when compared with controls or non-treated patients. The encouraging news is that these assays correlate with commonly available laboratory tests such as C-reactive protein, lactate dehydrogenase, and absolute neutrophil count. However, the problem of the absence of a diagnostic threshold remains.

Studies are currently exploring whether inhibiting the IL-8 pathway through blocking its receptors, i.e., CXCR1 and 2, may benefit relevant clinical outcomes of patients with acute inflammatory lung injury and related hypoxemia due to community-acquired pneumonia or ARDS

The second question is, assuming we detect high NETs or NET-related biomarkers, how do we intervene therapeutically? A possible answer is decreasing neutrophil sequestration in the pulmonary microcirculation and migration to the alveolar spaces in response to chemokine gradients originating in the injured lung via inflammatory mediators acting synergistically with microorganism end products. One of the most important such chemokines is IL-8. Studies are currently exploring whether inhibiting the IL-8 pathway through blocking its receptors, i.e., CXCR1 and 2, may benefit relevant clinical outcomes of patients with acute inflammatory lung injury and related hypoxemia due to community-acquired pneumonia or ARDS.