Dysregulated inflammasome activation contributes to respiratory infections and pathologic airway inflammation. Through basic and translational approaches involving murine models and human genetic epidemiology, we show here the importance of the different inflammasomes in regulating inflammatory responses in mice and humans with cystic fibrosis (CF), a life-threatening disorder of the lungs and digestive system. While both contributing to pathogen clearance, NLRP3 more than NLRC4 contributes to deleterious inflammatory responses in CF and correlates with defective NLRC4-dependent IL-1Ra production. Disease susceptibility in mice and microbial colonization in humans occurrs in conditions of genetic deficiency of NLRC4 or IL-1Ra and can be rescued by administration of the recombinant IL-1Ra, anakinra. These results indicate that pathogenic NLRP3 activity in CF could be negatively regulated by IL-1Ra and provide a proof-of-concept evidence that inflammasomes are potential targets to limit the pathological consequences of microbial colonization in CF.

T helper 9 (Th9) cells contribute to lung inflammation and allergy as sources of interleukin-9 (IL-9). However, the mechanisms by which IL-9/Th9 mediate immunopathology in the lung are unknown. Here we report an IL-9-driven positive feedback loop that reinforces allergic inflammation. We show that IL-9 increases IL-2 production by mast cells, which leads to expansion of CD25+ type 2 innate lymphoid cells (ILC2) and subsequent activation of Th9 cells. Blocking IL-9 or inhibiting CD117 (c-Kit) signalling counteracts the pathogenic effect of the described IL-9-mast cell-IL-2 signalling axis. Overproduction of IL-9 is observed in expectorates from cystic fibrosis (CF) patients, and a sex-specific variant of IL-9 is predictive of allergic reactions in female patients. Our results suggest that blocking IL-9 may be a therapeutic strategy to ameliorate inflammation associated with microbial colonization in the lung, and offers a plausible explanation for gender differences in clinical outcomes of patients with CF.

Liver involvement in Cystic Fibrosis (CF) is much less frequent than both pulmonary and pancreatic diseases that are present in 80-90% of CF patients; liver disease (LD) affects only one third of CF patients, however, because of the decreasing mortality from extrahepatic causes, its recognition and management is becoming a relevant clinical issue. Recent observations suggest that clinical expression of LD in CF may be influenced by genetic modifiers; their identification is an important issue because it may allow recognition of patients at risk for the development of LD at the time of diagnosis of CF and early institution of prophylactic strategies. Oral bile acid therapy, aimed at improving biliary secretion in terms of bile viscosity and bile acid composition, is currently the only available therapeutic approach for CF-associated LD. However, the impact of this therapy on the natural history of LD remains to be defined and long-term effectiveness on clinically relevant outcomes should be further investigated. Liver transplantation should be offered to CF patients with progressive liver failure and/or with life-threatening sequelae of portal hypertension, who also have mild pulmonary involvement that is expected to support long-term survival. The 1-year survival rate after transplantation in CF patients is approximately 80%, with beneficial effects on lung function, nutritional status, body composition and quality of life in most cases.

This study provides a link between tryptophan catabolism and lung immune homeostasis in murine CF, representing a proof-of-concept that targeting pathogenic inflammation via IDO-mimetic drugs may benefit patients with CF.

Nanocellulose (NC) is emerging as a highly promising nanomaterial for a wide range of applications. Moreover, many types of NC are produced, each exhibiting a slightly different shape, size, and chemistry. The main objective of this study was to compare cytotoxic effects of cellulose nanocrystals (CNC) and nanofibrillated cellulose (NCF). The human lung epithelial cells (A549) were exposed for 24 and 72 h to five different NC particles to determine how variations in properties contribute to cellular outcomes, including cytotoxicity, oxidative stress, and cytokine secretion. Our results showed that NCF were more toxic compared to CNC particles with respect to cytotoxicity and oxidative stress responses. However, exposure to CNC caused an inflammatory response with significantly elevated inflammatory cytokines/chemokines compared to NCF. Interestingly, cellulose staining indicated that CNC particles, but not NCF, were taken up by the cells. Furthermore, clustering analysis of the inflammatory cytokines revealed a similarity of NCF to the carbon nanofibers response and CNC to the chitin, a known immune modulator and innate cell activator. Taken together, the present study has revealed distinct differences between fibrillar and crystalline nanocellulose and demonstrated that physicochemical properties of NC are critical in determining their toxicity.

Objective: Diabetes frequently complicates cystic fibrosis (CF) without fasting hyperglycemia or despite spontaneous hypoglycemia (anecdotally ascribed to malnutrition), whose prevalence, clinical meaning, and relationship with glucose tolerance and clinical/nutritional status were not previously investigated. The relationship of CF genotype with insulin secretion control is also unclear. Design and methods: A total of 129 CF patients without stable diabetes received 188 oral glucose tolerance tests. Distribution of fasting plasma glucose (FPG), glucose, insulin and C-peptide responses, clinical/nutritional variables, and their relationships were analyzed. Results: FPG!60 mg/dl (3.3 mmo/l) was detected in 14% of studies and reactive hypoglycemia (PG!50 mg/dl (2.8 mmo/l)) in 15%. OGTT-based diabetes frequency was similar in the lowest quartile (Q1) and Q2-3 for FPG (10 and 8%), with higher glucose increment and area under the curve in Q1. Insulin and C-peptide levels were similar among FPG quartiles. Class I cystic fibrosis transmembrane conductance regulator mutation carriers had higher insulin concentrations than class II, especially in Q1 for FPG. Age, sex, nutritional, and anthropometric parameters including fat and lean body mass were unrelated to FPG. Lower FPG was associated with more frequent hospitalization rates (PZ0.002) and lower Shwachman scores (PZ0.041). Steroids weaning was accurately evaluated but then excluded as a possible cause of hypoglycemia. Conclusions/interpretation: Fasting asymptomatic hypoglycemia is frequent and possibly related to inappropriate insulin secretion control in class I mutation carriers. Low FPG does not exclude impaired glucose tolerance (IGT) and diabetes in CF and reflects worse clinical status.

A causal link between hyperactivation of RAGE and inflammation in CF has been observed, such that targeting pathogenic inflammation alleviated inflammation in CF and measurement of sRAGE levels could be a useful biomarker for RAGE-dependent inflammation in patients with CF.

Prolonged BF is beneficial in children with CF and may protect them against decline of pulmonary function. Particular attention should be paid to promote BF in infants with CF.