Cigarette smoke (CS), the primary risk factor of chronic obstructive pulmonary disease (COPD), leads to pulmonary inflammation through interleukin-1 receptor (IL-1R)I signalling, as determined using COPD mouse models. It is unclear whether interleukin (IL)-1a or IL-1b, activated by the Nlrp3/caspase-1 axis, is the predominant ligand for IL-1RI in CS-induced responses.We exposed wild-type mice (treated with anti-IL-1a or anti-IL-1b antibodies), and IL-1RI knockout (KO), Nlrp3 KO and caspase-1 KO mice to CS for 3 days or 4 weeks and evaluated pulmonary inflammation. Additionally, we measured the levels of IL-1a and IL-1b mRNA (in total lung tissue by RT-PCR) and protein (in induced sputum by ELISA) of never-smokers, smokers without COPD and patients with COPD.In CS-exposed mice, pulmonary inflammation was dependent on IL-1RI and could be significantly attenuated by neutralising IL-1a or IL-1b. Interestingly, CS-induced inflammation occurred independently of IL-1b activation by the Nlrp3/caspase-1 axis. In human subjects, IL-1a and IL-1b were significantly increased in total lung tissue and induced sputum of patients with COPD, respectively, compared with never-smokers.These results suggest that not only IL-1b but also IL-1a should be considered as an important mediator in CS-induced inflammation and COPD.

Inhalation of diesel exhaust particles (DEP) induces an inflammatory reaction in the lung; however, the mechanisms are largely unclear. IL-1β/IL-1RI signaling is crucial in several lung inflammatory responses. Typically, caspase-1 is activated within the NLRP3 inflammasome that recognizes several damage-associated molecular patterns, which results in cleavage of pro–IL-1β into mature IL-1β. In this study, we hypothesized that the NLRP3/caspase-1/IL-1β pathway is critical in DEP-induced lung inflammation. Upon DEP exposure, IL-1RI knockout mice had reduced pulmonary inflammation compared with wild-type mice. Similarly, treatment with rIL-1R antagonist (anakinra) and IL-1β neutralization impaired the DEP-induced lung inflammatory response. Upon DEP exposure, NLRP3 and caspase-1 knockout mice, however, showed similar IL-1β levels and comparable pulmonary inflammation compared with wild-type mice. In conclusion, these data show that the DEP-induced pulmonary inflammation acts through the IL-1β/IL-1RI axis. In addition, DEP initiates inflammation independent of the classical NLRP3/caspase-1 pathway, suggesting that other proteases might be involved.

Aim To provide a comprehensive update on the most prevalent, significant risk factors for neonatal brachial plexus palsy (NBPP). Method Cochrane CENTRAL, MEDLINE, Web of Science, Embase, and ClinicalTrials.gov were searched for relevant publications up to March 2019. Studies assessing risk factors of NBPP in relation to typically developing comparison individuals were included. Meta‐analysis was performed for the five most significant risk factors, on the basis of the PRISMA statement and MOOSE guidelines. Pooled odds ratios (ORs), 95% confidence intervals (CIs), and across‐study heterogeneity (I2) were reported. Reporting bias and quality of evidence was rated. In addition, we assessed the incidence of NBPP. Results Twenty‐two observational studies with a total sample size of 29 419 037 live births were selected. Significant risk factors included shoulder dystocia (OR 115.27; 95% CI 81.35–163.35; I2=92%), macrosomia (OR 9.75; 95% CI 8.29–11.46; I2=70%), (gestational) diabetes (OR 5.33; 95% CI 3.77–7.55; I2=59%), instrumental delivery (OR 3.8; 95% CI 2.77–5.23; I2=77%), and breech delivery (OR 2.49; 95% CI 1.67–3.7; I2=70%). Caesarean section appeared as a protective factor (OR 0.13; 95% CI 0.11–0.16; I2=41%). The pooled overall incidence of NBPP was 1.74 per 1000 live births. It has decreased in recent years. Interpretation The incidence of NBPP is decreasing. Shoulder dystocia, macrosomia, maternal diabetes, instrumental delivery, and breech delivery are risk factors for NBPP. Caesarean section appears as a protective factor. What this paper adds The overall incidence of neonatal brachial plexus palsy is 1.74 per 1000 live births. The incidence has declined significantly. Shoulder dystocia, macrosomia, maternal diabetes, instrumental delivery, and breech delivery are the main risk factors. Prevention is difficult owing to unpredictability and often labour‐related risk.

Chronic obstructive pulmonary disease (COPD) is characterized by infiltration of inflammatory cells, destruction of lung parenchyma, and airway wall remodeling. Hyaluronan (HA) is a component of the extracellular matrix, and low-molecular-weight (LMW) HA fragments have proinflammatory capacities. We evaluated the presence of HA in alveolar and airway walls of C57BL/6 mice that were exposed to air or cigarette smoke (CS) for 4 weeks (subacute) or 24 weeks (chronic). We measured deposition of the extracellular matrix proteins collagen and fibronectin in airway walls and determined the molecular weight of HA purified from lung tissue. In addition, we studied the expression of HA-modulating genes by RT-PCR. HA staining in alveolar walls was significantly enhanced upon chronic CS exposure, whereas HA levels in the airway walls were already significantly higher upon subacute CS exposure and remained elevated upon chronic CS exposure. This differed from the deposition of collagen and fibronectin, which are only elevated at the chronic time point. In lungs of CS-exposed mice, the molecular weight of HA clearly shifted toward more LMW HA fragments. CS exposure significantly increased the mRNA expression of the HA synthase gene Has3 in total lung tissue, whereas the expression of Has1 was decreased. These in vivo studies in an experimental model of COPD show that CS exposure leads to enhanced deposition of (mostly LMW) HA in alveolar and bronchial walls by altering the expression of HA-modulating enzymes. This may contribute to airway wall remodeling and pulmonary inflammation in COPD.

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