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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.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.

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.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.

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