Neutrophil-dominated inflammation plays an important role in many airway diseases including asthma, chronic obstructive pulmonary disease (COPD), bronchiolitis and cystic fibrosis. In cases of asthma where neutrophil-dominated inflammation is a major contributing factor to the disease, treatment with corticosteroids can be problematic as corticosteroids have been shown to promote neutrophil survival which, in turn, accentuates neutrophilic inflammation. In light of such cases, novel targeted medications must be developed that could control neutrophilic inflammation while still maintaining their antibacterial/anti-fungal properties, thus allowing individuals to maintain effective innate immune responses to invading pathogens. The aim of this review is to describe the molecular mechanisms of neutrophil apoptosis and how these pathways are modulated by glucocorticoids. These new findings are of potential clinical value and provide further insight into treatment of neutrophilic inflammation in lung disease.

The Molecular Mechanisms of Glucocorticoids-Mediated Neutrophil Survival

Extracellular superoxide dismutase (EC-SOD) is an abundant antioxidant in the lung and vascular walls. Previous studies have shown that EC-SOD attenuates lung injury in a diverse variety of lung injury models. In this study, we examined the role of EC-SOD in mediating lipopolysaccharide (LPS)-induced lung inflammation. We found that LPS-induced neutrophilic lung inflammation was exaggerated in EC-SOD–deficient mice and diminished in mice that overexpressed EC-SOD specifically in the lung. Similar patterns were seen for bronchoalveolar lavage cytokines, such as tumor necrosis factor–α, keratinocyte-derived chemokines, and macrophage inflammatory protein-2 as well as expression of lung intercellular adhesion molecule–1, vascular cell adhesion molecule–1, endothelial cell selectin, and platelet selectin. In a macrophage cell line, EC-SOD inhibited LPS-induced macrophage cytokine release, but did not alter expression of intercellular adhesion molecules in endothelial cells. These results suggest that EC-SOD p...

https://www.atsjournals.org/doi/pdf/10.1165/rcmb.2004-0057OC

Extracellular superoxide dismutase attenuates lipopolysaccharide-induced neutrophilic inflammation.

Background: Lower airway secretions from patients with bronchiectasis show inflammatory cell infiltration and increased proinflammatory mediators. The aim of this study was to investigate the effects of antibiotic treatment for exacerbations on neutrophil apoptosis and necrosis.

Methods: Sputum was induced from 15 subjects with idiopathic bronchiectasis at the beginning of an acute exacerbation and after intravenous antibiotic treatment. Neutrophil apoptosis and necrosis were assessed using flow cytometry and morphology and the supernatant was analysed for concentrations of inflammatory mediators.

Results: Neutrophil numbers (×106 cells/g sputum) in sputum were significantly greater on day 0 than on day 14 (median difference (95% confidence interval (CI)) 5.14 (1.27 to 8.46), p = 0.02). Controls had a significantly higher percentage of sputum macrophages than patients with bronchiectasis (day 0, 1.35 (95% CI 0.48 to 2.89), p = 0.004; day 14, 1.09 (95% CI 0.26 to 2.86), p = 0.02). The concentrations of tumour necrosis factor α (pg/ml), interleukin 8 (ng/ml), and neutrophil elastase (ng/ml) in sputum supernatant were significantly reduced on day 14 compared with day 0 (median difference −94 (95% CI −158 to −27), p = 0.005; −106 (95% CI −189 to −50), p = 0.0006; and −73 451 (95% CI −135 495 to −12 303), p = 0.02 respectively). Patients with bronchiectasis had a significantly lower percentage of cells which were neither apoptotic nor necrotic than healthy controls (both days, −38.8 (95% CI −49.6 to −8.5), p = 0.002; −45.0 (95% CI −58.0 to −34.1), p = 0.0003, respectively), and on day 14 they had a significantly higher percentage of secondary necrotic cells than healthy controls (40 (95% CI 11.6 to 57.5), p = 0.004).

Conclusions: This study shows that antibiotic treatment affects concentrations of proinflammatory mediators and cell death and clearance may be altered in bronchiectasis.

https://thorax.bmj.com/content/thoraxjnl/59/3/231.full.pdf

Neutrophil apoptosis, proinflammatory mediators and cell counts in bronchiectasis

Background
Nox-2 (also known as gp91phox), a subunit component of NADPH oxidases, generates reactive oxygen species (ROS). Nox-dependent ROS generation and nitric oxide (NO) release by microglia have been implicated in a variety of diseases in the central nervous system. Dexamethasone (Dex) has been shown to suppress the ROS production, NO release and inflammatory reaction of activated microglial cells. However, the underlying mechanisms remain unclear.

/pdf/dexamethasone-inhibits-the-nox-dependent-ros-production-via-1tsqxcb3yl.pdf

Dexamethasone inhibits the Nox-dependent ROS production via suppression of MKP-1-dependent MAPK pathways in activated microglia

Increased efficacy of immersion vaccination in fish with hyperosmotic pretreatment.

Neutrophils are completely differentiated cells that die in tissues a few days after they migrate from the vascular compartment as a consequence of a rigouous apoptotic program. Many of the mediators produced during an inflammatory response delay neutrophil apoptosis allowing a more efficient removal of microorganisms but also favoring the tissue damage by reactive oxygen species (ROS) and lysosomal proteins released by neutrophils. Glucocorticoids delay the apoptosis of neutrophils but the mechanisms are not completely understood. To investigate the inhibition of glucocorticoids on neutrophil apoptosis we have used the glucose/glucose oxidase (G/GO) system as a constant source of hydrogen peroxide. When neutrophils are incubated in the presence of the G/GO system, a significant acceleration of their apoptotic response is observed. Preincubation with 10−6 M, 10−7 M, 10−8 M or 10−9 M of dexamethasone, negatively modulated the spontaneous and G/GO induced apoptosis of neutrophils. Then the G/GO system is a useful model to simulate the oxidative stress of neutrophils, and that the effect of DXM on neutrophil apoptosis depends, at least in part, on blocking the proapoptotic effect of ROS.

Diana García de O

Papers

Dexamethasone inhibits apoptosis of human neutrophils induced by reactive oxygen species.