Characterizing the Neutrophilic Inflammation in Chronic Rhinosinusitis With Nasal Polyps

The mechanisms underlying neutrophilic inflammation in chronic rhinosinusitis with nasal polyps (CRSwNP) remain poorly investigated. This study aimed to examine the factors that contribute to tissue neutrophilia in CRSwNP. The numbers of neutrophils and active caspase-3-positive apoptotic neutrophils in sinonasal tissues were assessed via immunofluorescence staining. The 95th percentile of tissue neutrophil numbers in control subjects was selected as a cut-off to define neutrophil-high (Neu-high) or neutrophil-low (Neu-low) nasal polyps (NPs). The levels of 34 inflammatory mediators in sinonasal tissues were analyzed using Bio-Plex assay. Purified human peripheral blood neutrophils were incubated with nasal tissue homogenates, and the apoptotic neutrophils were assessed via flow cytometry. The cut-off for Neu-high NPs was >10 myeloperoxidase positive cells/high-power field. Compared with Neu-low NPs, Neu-high NPs had higher tissue levels of IL-1β, IL-1Ra, IL-6, IL-8, G-CSF, MCP-1, and MIP-1α, but lower levels of IL-5, IL-13, IgE, and eosinophils. Principal component and multiple correspondence analyses revealed mixed type 1, type 2, and type 3 endotypes for Neu-low NPs, and predominant type 1 and type 3 endotypes for Neu-high NPs. Neu-high NPs had lower percentages of apoptotic neutrophils than Neu-low NPs. The numbers of neutrophils and the percentages of apoptotic neutrophils correlated with G-CSF and IL-6 levels in the NPs. Tissue homogenates from Neu-high NPs, but not those from Neu-low NPs, suppressed neutrophil apoptosis in vitro, which was reversed by anti-G-CSF treatment. Tissue neutrophil numbers were associated with difficult-to-treat disease in patients with CRSwNP after surgery. We propose that G-CSF promotes neutrophilic inflammation by inhibiting neutrophil apoptosis in CRSwNP.

Effects of forages, dust exposure and proresolving lipids on airway inflammation in horses

OBJECTIVE To investigate the role of omega-3 polyunsaturated fatty acids (Ω-3)–derived proresolving lipid mediators (PRLM) in the resolution of mild airway inflammation in horses. ANIMALS 20 horses with mild airway inflammation. PROCEDURES Horses previously eating hay were fed hay pellets (low Ω-3 content; n = 10) or haylage (high Ω-3 content; 9) for 6 weeks. Dust exposure was measured in the breathing zone with a real-time particulate monitor. Bronchoalveolar lavage (BAL) was performed at baseline, week 3, and week 6. The effect of PRLM on neutrophil apoptosis and efferocytosis was examined in vitro. BAL fluid inflammatory cell proportions, apoptosis of circulating neutrophils, efferocytosis displayed by alveolar macrophages, and plasma lipid concentrations were compared between groups fed low and high amounts of Ω-3 by use of repeated measures of generalized linear models. RESULTS Dust exposure was significantly higher with hay feeding, compared to haylage and pellets, and equivalent between haylage and pellets. BAL fluid neutrophil proportions decreased significantly in horses fed haylage (baseline, 11.8 ± 2.4%; week 6, 2.5 ± 1.1%) but not pellets (baseline, 12.1 ± 2.3%; week 6, 8.5% ± 1.7%). At week 6, horses eating haylage had significantly lower BAL neutrophil proportions than those eating pellets, and a significantly lower concentration of stearic acid than at baseline. PRLM treatments did not affect neutrophil apoptosis or efferocytosis. CLINICAL RELEVANCE Despite similar reduction in dust exposure, horses fed haylage displayed greater resolution of airway inflammation than those fed pellets. This improvement was not associated with increased plasma Ω-3 concentrations. Feeding haylage improves airway inflammation beyond that due to reduced dust exposure, though the mechanism remains unclear.

Simvastatin boosts neutrophil apoptosis and ameliorates secondary brain injury following intracerebral hemorrhage via LXA4/FPR2/p38 MAPK pathway

Statins, in addition to their well-known lipid-lowering effects, have also shown a wide range of neuroprotective effects in recent years. We previously found that simvastatin effectively attenuated intracerebral hemorrhage (ICH)-induced secondary brain injury in rats. This study aims to elucidate the underlying mechanism. The animal model was established in adult male Sprague–Dawley rats by an injection of autologous blood, then randomly treated with simvastatin or vehicle. Then, a series of experiments were conducted to investigate the involvement of lipoxin A4 (LXA4) / formyl-peptide receptor 2 (FPR2) / p38 MAPK signaling pathway in simvastatin-triggered neutrophil apoptosis. Results show that simvastatin significantly elevated the level of LXA4 (an endogenous FPR2 agonist) in plasm in early stage of ICH. Exogenous LXA4 administration effectively promoted circulating neutrophil apoptosis, reduced the neutrophil count in both peripheral blood and perihematomal area, as well as ameliorated neuroinflammation and brain injury after ICH, which in line with the effect of simvastatin. Moreover, similar to simvastatin, the exogenous LXA4 markedly down-regulated the phosphorylation level of p38 and the Mcl-1/Bax ratio (the decreased ratio represents pro-apoptosis) in circulating neutrophils of ICH rat. Notably, all above effects of simvastatin on ICH were significantly abolished by Boc-2, a selective antagonist for FPR2. Moreover, simvastatin led to a similar reduction of Mcl-1/Bax ratio as SB203580 (p38 MAPK inhibitor), but it was abolished by P79350 (p38 MAPK agonist). Collectively, these results suggest that simvastatin boosts neutrophils apoptosis and alleviates subsequent neuroinflammation following ICH may via upregulating LXA4 in plasma through the FPR2/p38 MAPK signaling pathway.

The IL-1 Receptor Is Required to Maintain Neutrophil Viability and Function During Aspergillus fumigatus Airway Infection

Aspergillus fumigatus airway infections are associated with increased rates of hospitalizations and declining lung function in patients with chronic lung disease. While the pathogenesis of invasive A. fumigatus infections is well studied, little is known about the development and progression of airway infections. Previous studies have demonstrated a critical role for the IL-1 cytokines, IL-1α and IL-1β in enhancing pulmonary neutrophil recruitment during invasive aspergillosis. Here we use a mouse model of A. fumigatus airway infection to study the role of these IL-1 cytokines in immunocompetent mice. In the absence of IL-1 receptor signaling, mice exhibited reduced numbers of viable pulmonary neutrophils and increased levels of neutrophil apoptosis during fungal airway infection. Impaired neutrophil viability in these mice was associated with reduced pulmonary and systemic levels of G-CSF, and treatment with G-CSF restored both neutrophil viability and resistance to A. fumigatus airway infection. Taken together, these data demonstrate that IL-1 dependent G-CSF production plays a key role for host resistance to A. fumigatus airway infection through suppressing neutrophil apoptosis at the site of infection.