Status epilepticus (SE) is one of the most serious manifestations of epilepsy. Systemic inflammation and damage of blood-brain barrier (BBB) are etiologic cofactors in the pathogenesis of pilocarpine SE while acute osmotic disruption of the BBB is sufficient to elicit seizures. Whether an inflammatory-vascular-BBB mechanism could apply to the lithium–pilocarpine model is unknown. LiCl facilitated seizures induced by low-dose pilocarpine by activation of circulating T-lymphocytes and mononuclear cells. Serum IL-1β levels increased and BBB damage occurred concurrently to increased theta EEG activity. These events occurred prior to SE induced by cholinergic exposure. SE was elicited by lithium and pilocarpine irrespective of their sequence of administration supporting a common pathogenetic mechanism. Since IL-1β is an etiologic trigger for BBB breakdown and its serum elevation occurs before onset of SE early after LiCl and pilocarpine injections, we tested the hypothesis that intravenous administration of IL-1 receptor antagonists (IL-1ra) may prevent pilocarpine-induced seizures. Animals pre-treated with IL-1ra exhibited significant reduction of SE onset and of BBB damage. Our data support the concept of targeting systemic inflammation and BBB for the prevention of status epilepticus.

Information on the clinical traits associated with bronchial neutrophilia in asthma is scant, preventing its recognition and adequate treatment. We aimed to assess the clinical, functional and biological features of neutrophilic asthma and identify possible predictors of bronchial neutrophilia.The inflammatory phenotype of 70 mild-to-severe asthma patients was studied cross-sectionally based on the eosinophilic/neutrophilic counts in their bronchial lamina propria. Patients were classified as neutrophilic or non-neutrophilic. Neutrophilic asthma patients (neutrophil count cut-off: 47.17 neutrophils·mm−2; range: 47.17–198.11 neutrophils·mm−2; median: 94.34 neutrophils·mm−2) were further classified as high (≥94.34 neutrophils·mm−2) or intermediate (47.17– <94.34 neutrophils·mm−2). The effect of smoking ≥10 pack-years was also assessed.Neutrophilic asthma patients (n=38; 36 mixed eosinophilic/neutrophilic) had greater disease severity, functional residual capacity, inhaled corticosteroid (ICS) dose and exacerbations, and lower forced vital capacity (FVC) % pred and forced expiratory volume in 1 s (FEV1) reversibility than non-neutrophilic asthma patients (n=32; 28 eosinophilic and four paucigranulocytic). Neutrophilic asthma patients had similar eosinophil counts, increased bronchial CD8+, interleukin (IL)-17-F+ and IL-22+ cells, and decreased mast cells compared with non-neutrophilic asthma patients. FEV1 and FVC reversibility were independent predictors of bronchial neutrophilia in our cohort. High neutrophilic patients (n=21) had increased serum IgE levels, sensitivity to perennial allergens, exacerbation rate, oral corticosteroid dependence, and CD4+ and IL-17F+ cells in their bronchial mucosa. Excluding smokers revealed increased IL-17A+ and IL-22+ cells in highly neutrophilic patients.We provide new evidence linking the presence of high bronchial neutrophilia in asthma to an adaptive immune response associated with allergy (IgE) and IL-17/22 cytokine expression. High bronchial neutrophilia may discriminate a new endotype of asthma. Further research is warranted on the relationship between bronchoreversibility and bronchial neutrophilia.

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Dupilumab is a fully humanized monoclonal antibody, capable of inhibiting intracellular signaling of both interleukin (IL)-4 and IL-13. These are two molecules that, together with other proinflammatory cytokines such as IL-5 and eotaxins, play a pivotal role in orchestrating the airway inflammatory response defined as Type 2 (T2) inflammation, driven by Th2 or Type 2 innate lymphoid cells, which is the major feature of the T2 high asthma phenotype. The dual inhibition of IL-4 and IL-13 activities is due to the blockade of type II IL-4 receptor through the binding of dupilumab with the subunit IL-4Rα. This results in the repression of STAT6 and in the suppression of subsequent de novo formation of several molecules involved in the T2 inflammatory signature. Several clinical trials tested the efficacy and safety of dupilumab in large populations of uncontrolled severe asthmatics, revealing significant improvements in lung function, asthma control, and exacerbation rate. Similar results were reported when dupilumab was employed in patients harboring pathogenetic processes related to T2 immune response, such as atopic dermatitis and chronic rhinosinusitis. In this review, we provide an overview of the recent research in the field of respiratory medicine about dupilumab mechanism of action and its effects.