Newborn Cystic Fibrosis Pigs Have a Blunted Early Response to an Inflammatory Stimulus

Abstract

Rationale: Studies suggest that inappropriate responses to proinflammatory stimuli might contribute to inflammation in cystic fibrosis (CF) lungs. However, technical challenges have made it difficult to distinguish whether altered responses in CF airways are an intrinsic defect or a secondary effect of chronic disease in their tissue of origin. The CF pig model provides an opportunity to study the inflammatory responses of CF airways at birth, before the onset of infection and inflammation.Objectives: To test the hypothesis that acute inflammatory responses are perturbed in porcine CF airways. Methods:We investigated the inflammatory responses of newborn CF and non-CF pig airways following a 4-hour exposure to heatkilled Staphylococcus aureus, in vivo and in vitro.Measurements and Main Results: Following an in vivo S. aureus challenge, markers of inflammation were similar between CF and littermate control animals through evaluation of bronchoalveolar lavage and tissues. However, transcriptome analysis revealed genotype-dependent differences as CF pigs showed a diminished host defense response compared with their non-CF counterparts. Furthermore, CF pig airways exhibited an increase in apoptotic pathways and a suppression of ciliary and flagellar biosynthetic pathways. Similar differences were observed in cultured airway epithelia from CF and non-CF pigs exposed to the stimulus.Conclusions: Transcriptome profiling suggests that acute inflammatory responses are dysregulated in the airways of newborn CF pigs.

The Role of Specialized Pro-Resolving Mediators in Cystic Fibrosis Airways Disease

“…Abnormal SPM production or function have been related to widely occurring disorders, including CF airway disease. The airways of CF patients showed a decreased production of SPMs even in the absence of pathogens, which is consistent with other reports showing that inflammation in CF might not only be a consequence of chronic infection but could be related to intrinsic abnormalities of the inflammatory response ( Muhlebach et al, 1999 ; Muhlebach and Noah, 2002 ; Karp et al, 2004 ; Ringholz et al, 2014 ; Bartlett et al, 2016 ; Isopi et al, 2020 ). The two SPMs, lipoxin A4 (LXA4) and resolvin D1 (RvD1), have the unique ability to restore the airway surface hydration, to damp the pro-inflammatory program and to fight infection in CF airways circumventing the most difficult aspects of CF pathophysiology ( Karp et al, 2004 ; Grumbach et al, 2009 ; Verrière et al, 2012 ; Buchanan et al, 2013 ; Al-Alawi et al, 2014 ; Higgins et al, 2014 ; Higgins et al, 2016 ; Codagnone et al, 2017 ; Ringholz et al, 2018 ; Isopi et al, 2020 ).…”

“…Among the proteins encoded by the CF modifier genes, some have direct protein-protein interaction with CFTR and/or are involved in immune response ( Tugores et al, 2001 ; Wright et al, 2011 ; Stanke et al, 2014 ; Corvol et al, 2015 ). The trachea of CF and non-CF newborn pigs when challenged by an inflammatory stimulus revealed differential transcriptomes ( Bartlett et al, 2016 ). Therefore, beyond ion transport abnormalities, intrinsic immune abnormalities related to CFTR dysfunction could be involved in the pathogenesis of the CF airway disease.…”

Role of CFTR in epithelial physiology

“…However, since the development of the CF pig model, it has been shown that inflammatory markers in bronchoalveolar lavages (BALs) of the lung did not differ from non-CF piglets, although the CF pigs showed a marked increased susceptibility to infection [102]. However, a recent transcriptomic study showed that although levels of inflammatory markers did not change, CF pig airways responded with a diminished host defence response after infection with S. aureus , when compared to non-CF pigs [103]. …”

Correction of lung inflammation in a F508del CFTR murine cystic fibrosis model by the sphingosine-1-phosphate lyase inhibitor LX2931

“…In CF infants with early-stage lung disease, CT scans show bronchial thickening and distal air-trapping even in the absence of apparent bacterial infection (41,68), suggesting unprovoked inflammation in CF lung. In newborn CF piglets, however, a CF-like lung pathology develops within months without enhanced neutrophil infiltration prior to infection, arguing against significant sterile inflammation in newborn CF pig lung (2,6,69). However, no detailed quantitative analysis of tissue DC and other myeloid populations by FACS was reported in early stages of disease in either CF pig or human.…”