An Activated Immune and Inflammatory Response Targets the Pancreas of Newborn Pigs with Cystic Fibrosis

Abstract

Background/Aims: In cystic fibrosis (CF), pancreatic disease begins in utero and progresses over time to complete destruction of the organ. Although inflammatory cells have been detected in the pancreas of humans and pigs with CF, their subtypes have not been characterized. Methods: Using four-color flow cytometry, we analyzed the surface antigens of leukocytes in pancreas, blood, and mesenteric lymph nodes (MLN) of newborn pigs with CF (CFTR^–/– and CFTR^Δ^F508/^Δ^F508) and in those without CF (CFTR^+/–, CFTR^+/^Δ^F508, CFTR^+/+). Pancreatic histopathology was examined with HE stain. Results: CF pig pancreas had patchy distribution of inflammatory cells with neutrophils/macrophages in dilated acini, and lymphocytes in the interstitium compared to non-CF. B cells, effector (MHC-II⁺) and cytotoxic (CD2⁺CD8⁺) γδ T cells, activated (MHC-II⁺ and/or CD25⁺) and effector (CD4⁺CD8⁺) αβ T helper cells, effector natural killer cells (MHC-II⁺CD3^–CD8⁺), and monocytes/macrophages and neutrophils were increased in the CF pig pancreas compared to pigs without CF. Blood and MLN leukocyte populations were not different between CF and non-CF pigs. Conclusions: We discovered an activated immune response that was specific to the pancreas of newborn CF pigs; inflammation was not systemic. The presence of both innate and adaptive immune cells suggests that the disease process is complex and extensive.

Acute toxicity of silver and carbon nanoaerosols to normal and cystic fibrosis human bronchial epithelial cells

“…Our data also support the hypothesis that CF airway hyperinflammation is a direct consequence of lacking functional CFTR rather than an indirect effect of impaired mucociliary clearance and bacterial colonization (Machen, 2006;Ratjen, 2006;Stoltz et al, 2010;Sun et al, 2010). Enhanced inflammatory responses without apparent infection were also found in newborn pigs or infants with CF (Abu- El-Haija et al, 2011;Dakin et al, 2002;Rosenfeld et al, 2001). In addition, experimental restoration of CFTR function in CF cells was shown to decrease the hyperinflammatory state (Eidelman et al, 2001;Van Goor et al, 2006).…”

Mapping of long-range INS promoter interactions reveals a role for calcium-activated chloride channel ANO1 in insulin secretion

“…Nonetheless, we note that ANO1 (TMEM16A) overexpression has been shown to suppress proinflammatory cytokine expression in human cystic fibrosis bronchial epithelia (44). Another study identified an activated immune response specific to the pancreas in newborn pigs with cystic fibrosis (45). It seems possible that defects in the ANO1 gene or in its expression in pancreatic islets could affect cytokine expression and evoke an immune response resulting in β cell death.…”

Cigarette smoke and CFTR: implications in the pathogenesis of COPD

“…Further support for the importance of CFTR in maintaining the physiological environment of tissues comes from studies on the pancreas of newborn CF pigs that indicate the presence of increased neutrophil, macrophage, and lymphocyte infiltration in dilated acini and in the interstitium, without an apparent bacterial infection. This suggests the proinflammatory nature of mucus stasis itself (3). Despite these reports, whether loss of CFTR itself or the subsequent infection promotes the inflammatory response remains controversial.…”