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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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Histology of the lung and BAL inflammatory cells. a, b Histology of normal (a) and lipopolysaccharide (LPS) injured (b) lung (H-E staining, objective magnification ×40, bar 50 μm). c, d Percentage of alveolar macrophages and neutrophils in BAL cells under normal conditions and LPS-induced acute lung injury (d) at 24 h. MΦ Alveolar macrophages, N neutrophils
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Fig1: Histology of the lung and BAL inflammatory cells. a, b Histology of normal (a) and lipopolysaccharide (LPS) injured (b) lung (H-E staining, objective magnification ×40, bar 50 μm). c, d Percentage of alveolar macrophages and neutrophils in BAL cells under normal conditions and LPS-induced acute lung injury (d) at 24 h. MΦ Alveolar macrophages, N neutrophils

Mentions: To study the effect of LPS-induced lung inflammation on CFTR mRNA expression, we collected lung tissue and BAL cells separately 24 h after wild-type mice were challenged intratracheally with either PBS or LPS (5 mg/kg). Histologically, LPS-injured lungs displayed pulmonary edema, neutrophil infiltration, and hemorrhage (Fig. 1a, b) and the mRNA of cytokines (MCP-1, MIP-2, IL-1β, and TNF-α) increased 75, 1,029, 30, and 30-fold respectively (Table 1). Gene transcripts of CFTR were detected, but there was no difference between the PBS control and LPS-challenged lung tissue (Table 1). In the BAL inflammatory cells, LPS challenge switched the cell population from alveolar macrophages to predominantly neutrophils (Fig. 1c, d) and the mRNA of several cytokines (MCP-1, MIP-2, IL-1β, and TNF-α) in the BAL cells increased, by 35, 494, 93, and 18.9-fold respectively (P < 0.01, Table 2). The mRNA for CFTR in the inflammatory cells was elevated three-fold after LPS challenge (P < 0.05, Table 2). These data suggest that the acute inflammatory cells (mainly neutrophils in the BAL) that respond to LPS-induced lung inflammation and injury are able to upregulate CFTR transcripts.Fig. 1


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)

Histology of the lung and BAL inflammatory cells. a, b Histology of normal (a) and lipopolysaccharide (LPS) injured (b) lung (H-E staining, objective magnification ×40, bar 50 μm). c, d Percentage of alveolar macrophages and neutrophils in BAL cells under normal conditions and LPS-induced acute lung injury (d) at 24 h. MΦ Alveolar macrophages, N neutrophils
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3116128&req=5

Fig1: Histology of the lung and BAL inflammatory cells. a, b Histology of normal (a) and lipopolysaccharide (LPS) injured (b) lung (H-E staining, objective magnification ×40, bar 50 μm). c, d Percentage of alveolar macrophages and neutrophils in BAL cells under normal conditions and LPS-induced acute lung injury (d) at 24 h. MΦ Alveolar macrophages, N neutrophils
Mentions: To study the effect of LPS-induced lung inflammation on CFTR mRNA expression, we collected lung tissue and BAL cells separately 24 h after wild-type mice were challenged intratracheally with either PBS or LPS (5 mg/kg). Histologically, LPS-injured lungs displayed pulmonary edema, neutrophil infiltration, and hemorrhage (Fig. 1a, b) and the mRNA of cytokines (MCP-1, MIP-2, IL-1β, and TNF-α) increased 75, 1,029, 30, and 30-fold respectively (Table 1). Gene transcripts of CFTR were detected, but there was no difference between the PBS control and LPS-challenged lung tissue (Table 1). In the BAL inflammatory cells, LPS challenge switched the cell population from alveolar macrophages to predominantly neutrophils (Fig. 1c, d) and the mRNA of several cytokines (MCP-1, MIP-2, IL-1β, and TNF-α) in the BAL cells increased, by 35, 494, 93, and 18.9-fold respectively (P < 0.01, Table 2). The mRNA for CFTR in the inflammatory cells was elevated three-fold after LPS challenge (P < 0.05, Table 2). These data suggest that the acute inflammatory cells (mainly neutrophils in the BAL) that respond to LPS-induced lung inflammation and injury are able to upregulate CFTR transcripts.Fig. 1

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