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Role of CFTR expressed by neutrophils in modulating acute lung inflammation and injury in mice.

Su X, Looney MR, Su HE, Lee JW, Song Y, Matthay MA - Inflamm. Res. (2011)

Bottom Line: Cystic fibrosis transmembrane conductance regulator (CFTR) regulates infection and inflammation.Wild-type mice were reconstituted with F508del neutrophils or bone marrow and then intratracheally challenged with LPS to observe lung inflammatory response.Pharmacologic inhibition and genetic mutation of CFTR in neutrophils activated NF-κB and facilitated macrophage inflammatory protein-2 (MIP-2) and tumor necrosis factor-α (TNF-α) production.

View Article: PubMed Central - PubMed

Affiliation: Cardiovascular Research Institute, University of California, San Francisco, HSW 825, 505 Parnassus AVE, San Francisco, CA 94143-0130, USA. suxiao1@yahoo.com

ABSTRACT

Objective and design: Cystic fibrosis transmembrane conductance regulator (CFTR) regulates infection and inflammation. In this study, we investigated whether a lack of functional CFTR in neutrophils would promote lipopolysaccharide (LPS)-induced lung inflammation and injury.

Materials and methods: CFTR-inhibited or F508del-CFTR-mutated neutrophils were stimulated with LPS and cultured to evaluate production of cytokines and NF-κB activation. Wild-type mice were reconstituted with F508del neutrophils or bone marrow and then intratracheally challenged with LPS to observe lung inflammatory response.

Results: Pharmacologic inhibition and genetic mutation of CFTR in neutrophils activated NF-κB and facilitated macrophage inflammatory protein-2 (MIP-2) and tumor necrosis factor-α (TNF-α) production. Wild-type mice reconstituted with F508del neutrophils and bone marrow had more severe lung inflammation and injury after LPS challenge compared to wild-type mice receiving wild-type neutrophils or bone marrow reconstitution.

Conclusions: Lack of functional CFTR in neutrophils can promote LPS-induced acute lung inflammation and injury.

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Related in: MedlinePlus

Greater neutrophil transmigration, higher epithelial and vascular permeability, and chemokine production in the wild-type mice receiving F508del bone marrow transplantation and intratracheal LPS challenge. a BAL myeloperoxidase (MPO) using a kinetic assay. *P < 0.05 for WT/WT vs WT/F508del, F508del/WT, and F508del/F508del group. b Comparison of MPO levels in the BAL by calculating area under curve to confirm the significant differences between WT/WT and the other groups. c BAL protein levels. P < 0.05 or 0.01 for WT/WT vs WT/F508del, F508del/WT, and F508del/F508del group. d BAL MIP-2 levels. P < 0.05 or 0.01 for WT/WT vs WT/F508del, and F508del/F508del group. Data were pooled from at least three independent experiments. N = 4–6 in each group. Values are mean ± SD
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Fig8: Greater neutrophil transmigration, higher epithelial and vascular permeability, and chemokine production in the wild-type mice receiving F508del bone marrow transplantation and intratracheal LPS challenge. a BAL myeloperoxidase (MPO) using a kinetic assay. *P < 0.05 for WT/WT vs WT/F508del, F508del/WT, and F508del/F508del group. b Comparison of MPO levels in the BAL by calculating area under curve to confirm the significant differences between WT/WT and the other groups. c BAL protein levels. P < 0.05 or 0.01 for WT/WT vs WT/F508del, F508del/WT, and F508del/F508del group. d BAL MIP-2 levels. P < 0.05 or 0.01 for WT/WT vs WT/F508del, and F508del/F508del group. Data were pooled from at least three independent experiments. N = 4–6 in each group. Values are mean ± SD

Mentions: To isolate the effects of CFTR dysfunction in vivo, we created bone marrow chimeras using wild-type and F508del mice. Two months after bone marrow transplantation, WT/WT (wild-type mice receiving wild-type bone marrow), WT/F508del (wild-type mice receiving F508del bone marrow), F508del/WT (F508del mice receiving wild-type bone marrow), and F508del/F508del mice (F508del recipient receiving F508del bone marrow) were challenged intratracheally with LPS. At 24 h after LPS, BAL MPO and protein levels were elevated in all groups compared to the WT/WT group (Fig. 8a–c). Higher MIP-2 production was also found in the airspaces of the WT/F508del group and F508del/F508del groups compared to the WT/WT group (Fig. 8c).Fig. 8


Role of CFTR expressed by neutrophils in modulating acute lung inflammation and injury in mice.

Su X, Looney MR, Su HE, Lee JW, Song Y, Matthay MA - Inflamm. Res. (2011)

Greater neutrophil transmigration, higher epithelial and vascular permeability, and chemokine production in the wild-type mice receiving F508del bone marrow transplantation and intratracheal LPS challenge. a BAL myeloperoxidase (MPO) using a kinetic assay. *P < 0.05 for WT/WT vs WT/F508del, F508del/WT, and F508del/F508del group. b Comparison of MPO levels in the BAL by calculating area under curve to confirm the significant differences between WT/WT and the other groups. c BAL protein levels. P < 0.05 or 0.01 for WT/WT vs WT/F508del, F508del/WT, and F508del/F508del group. d BAL MIP-2 levels. P < 0.05 or 0.01 for WT/WT vs WT/F508del, and F508del/F508del group. Data were pooled from at least three independent experiments. N = 4–6 in each group. Values are mean ± SD
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Fig8: Greater neutrophil transmigration, higher epithelial and vascular permeability, and chemokine production in the wild-type mice receiving F508del bone marrow transplantation and intratracheal LPS challenge. a BAL myeloperoxidase (MPO) using a kinetic assay. *P < 0.05 for WT/WT vs WT/F508del, F508del/WT, and F508del/F508del group. b Comparison of MPO levels in the BAL by calculating area under curve to confirm the significant differences between WT/WT and the other groups. c BAL protein levels. P < 0.05 or 0.01 for WT/WT vs WT/F508del, F508del/WT, and F508del/F508del group. d BAL MIP-2 levels. P < 0.05 or 0.01 for WT/WT vs WT/F508del, and F508del/F508del group. Data were pooled from at least three independent experiments. N = 4–6 in each group. Values are mean ± SD
Mentions: To isolate the effects of CFTR dysfunction in vivo, we created bone marrow chimeras using wild-type and F508del mice. Two months after bone marrow transplantation, WT/WT (wild-type mice receiving wild-type bone marrow), WT/F508del (wild-type mice receiving F508del bone marrow), F508del/WT (F508del mice receiving wild-type bone marrow), and F508del/F508del mice (F508del recipient receiving F508del bone marrow) were challenged intratracheally with LPS. At 24 h after LPS, BAL MPO and protein levels were elevated in all groups compared to the WT/WT group (Fig. 8a–c). Higher MIP-2 production was also found in the airspaces of the WT/F508del group and F508del/F508del groups compared to the WT/WT group (Fig. 8c).Fig. 8

Bottom Line: Cystic fibrosis transmembrane conductance regulator (CFTR) regulates infection and inflammation.Wild-type mice were reconstituted with F508del neutrophils or bone marrow and then intratracheally challenged with LPS to observe lung inflammatory response.Pharmacologic inhibition and genetic mutation of CFTR in neutrophils activated NF-κB and facilitated macrophage inflammatory protein-2 (MIP-2) and tumor necrosis factor-α (TNF-α) production.

View Article: PubMed Central - PubMed

Affiliation: Cardiovascular Research Institute, University of California, San Francisco, HSW 825, 505 Parnassus AVE, San Francisco, CA 94143-0130, USA. suxiao1@yahoo.com

ABSTRACT

Objective and design: Cystic fibrosis transmembrane conductance regulator (CFTR) regulates infection and inflammation. In this study, we investigated whether a lack of functional CFTR in neutrophils would promote lipopolysaccharide (LPS)-induced lung inflammation and injury.

Materials and methods: CFTR-inhibited or F508del-CFTR-mutated neutrophils were stimulated with LPS and cultured to evaluate production of cytokines and NF-κB activation. Wild-type mice were reconstituted with F508del neutrophils or bone marrow and then intratracheally challenged with LPS to observe lung inflammatory response.

Results: Pharmacologic inhibition and genetic mutation of CFTR in neutrophils activated NF-κB and facilitated macrophage inflammatory protein-2 (MIP-2) and tumor necrosis factor-α (TNF-α) production. Wild-type mice reconstituted with F508del neutrophils and bone marrow had more severe lung inflammation and injury after LPS challenge compared to wild-type mice receiving wild-type neutrophils or bone marrow reconstitution.

Conclusions: Lack of functional CFTR in neutrophils can promote LPS-induced acute lung inflammation and injury.

Show MeSH
Related in: MedlinePlus