The role of neutrophils and epidermal growth factor receptors in lipopolysaccharide-induced mucus hypersecretion

Sang Myeon Bak, Soo Yeon Park, Gyu Young Hur, Seung Heon Lee, Je Hyeong Kim, Sang Yeub Lee, Chol Shin, Jae Jeong Shim, Kwang Ho In, Kyung Ho Kang, Se Hwa Yoo

Research output: Contribution to journalArticle

Abstract

Background: Goblet cell hyperplasia is a critical pathological feature in hypersecretory diseases of the airways. A bacterial infection of the lung is also known to induce inflammatory responses, which can lead to the overproduction of mucus. Recently, mucin synthesis in the airways has been reported to be regulated by neutrophilic inflammation-induced epidermal growth factor receptor (EGFR) expression and activation. In addition, it was reported that migration of the activated neutrophils is dependent on the matrix metalloproteinases (MMPs), especially MMP-9. In this study, bacterial lipopolysaccharide (LPS)-induced goblet cell hyperplasia and mucus hypersecretion by EGFR cascade, resulting from the MMPs-dependent neutrophilic inflammation were investigated in the rat airways. Methods: Pathogen-free Sprague-Dawley rats were studied in vivo. Various concentrations of LPS were instilled into the trachea in 300ℓ PBS (LPS group). Sterile PBS (300ℓ) was instilled into the trachea of the control animals (control group). The airways were examined on different days after instilling LPS. For an examination of the relationship between the LPS-induced goblet cell hyperplasia and MMPs, the animals were pretreated 3 days prior to the LPS instillation and daily thereafter with the matrix metalloproteinase inhibitor (MMPI; 20 mg/Kg/day of CMT-3; Collagenex Pharmaceuticals, USA). The neutrophilic infiltration was quantified as a number in five high power fields (HPF). The alcian blue/periodic acid-Schiff (AB/PAS) stain were performed for the mucus glycoconjugates and the immunohistochemical stains were performed for MUC5AC, EGFR and MMP-9. Their expressions were quantified by an image analysis program and were expressed by the percentage of the total bronchial epithelial area. Results: The instillation of LPS induced AB/PAS and MUC5AC staining in the airway epithelium in a time- and dose-dependent manner. Treatment with the MMPI prevented the LPS-induced goblet cell hyperplasia significantly. The instillation of LPS into the trachea induced also EGFR expression in the airway epithelium. The control airway epithelium contained few leukocytes, but the intratracheal instillation of LPS resulted in a neutrophilic recruitment. A pretreatment with MMPI prevented neutrophilic recruitment, EGFR expression, and goblet cell hyperplasia in the LPS-instilled airway epithelium. Conclusion: Matrix metalloproteinase is involved in LPS-induced mucus hypersecretion, resulting from a neutrophilic inflammation and EGFR cascade. These results suggest a potential therapeutic role of MMPI in the treatment of mucus hypersecretion that were associated with a bacterial infection of the airways.

Original languageEnglish
Pages (from-to)80-90
Number of pages11
JournalTuberculosis and Respiratory Diseases
Volume54
Issue number1
Publication statusPublished - 2003 Jan 1

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Mucus
Lipopolysaccharides
Neutrophils
Goblet Cells
Epidermal Growth Factor Receptor
MMPI
Hyperplasia
Matrix Metalloproteinases
Epithelium
Trachea
Alcian Blue
Periodic Acid
Matrix Metalloproteinase 9
Inflammation
Bacterial Infections
ErbB Receptors
Coloring Agents
Airway Management
Glycoconjugates
Matrix Metalloproteinase Inhibitors

Keywords

  • Epidermal growth factor receptor
  • Goblet cell hyperplasia
  • Lipopolysaccharide
  • Mucus hypersecretion
  • Neutrophilic inflammation

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Cite this

@article{eef96c67e449464faeb4a2f3a1da3386,
title = "The role of neutrophils and epidermal growth factor receptors in lipopolysaccharide-induced mucus hypersecretion",
abstract = "Background: Goblet cell hyperplasia is a critical pathological feature in hypersecretory diseases of the airways. A bacterial infection of the lung is also known to induce inflammatory responses, which can lead to the overproduction of mucus. Recently, mucin synthesis in the airways has been reported to be regulated by neutrophilic inflammation-induced epidermal growth factor receptor (EGFR) expression and activation. In addition, it was reported that migration of the activated neutrophils is dependent on the matrix metalloproteinases (MMPs), especially MMP-9. In this study, bacterial lipopolysaccharide (LPS)-induced goblet cell hyperplasia and mucus hypersecretion by EGFR cascade, resulting from the MMPs-dependent neutrophilic inflammation were investigated in the rat airways. Methods: Pathogen-free Sprague-Dawley rats were studied in vivo. Various concentrations of LPS were instilled into the trachea in 300ℓ PBS (LPS group). Sterile PBS (300ℓ) was instilled into the trachea of the control animals (control group). The airways were examined on different days after instilling LPS. For an examination of the relationship between the LPS-induced goblet cell hyperplasia and MMPs, the animals were pretreated 3 days prior to the LPS instillation and daily thereafter with the matrix metalloproteinase inhibitor (MMPI; 20 mg/Kg/day of CMT-3; Collagenex Pharmaceuticals, USA). The neutrophilic infiltration was quantified as a number in five high power fields (HPF). The alcian blue/periodic acid-Schiff (AB/PAS) stain were performed for the mucus glycoconjugates and the immunohistochemical stains were performed for MUC5AC, EGFR and MMP-9. Their expressions were quantified by an image analysis program and were expressed by the percentage of the total bronchial epithelial area. Results: The instillation of LPS induced AB/PAS and MUC5AC staining in the airway epithelium in a time- and dose-dependent manner. Treatment with the MMPI prevented the LPS-induced goblet cell hyperplasia significantly. The instillation of LPS into the trachea induced also EGFR expression in the airway epithelium. The control airway epithelium contained few leukocytes, but the intratracheal instillation of LPS resulted in a neutrophilic recruitment. A pretreatment with MMPI prevented neutrophilic recruitment, EGFR expression, and goblet cell hyperplasia in the LPS-instilled airway epithelium. Conclusion: Matrix metalloproteinase is involved in LPS-induced mucus hypersecretion, resulting from a neutrophilic inflammation and EGFR cascade. These results suggest a potential therapeutic role of MMPI in the treatment of mucus hypersecretion that were associated with a bacterial infection of the airways.",
keywords = "Epidermal growth factor receptor, Goblet cell hyperplasia, Lipopolysaccharide, Mucus hypersecretion, Neutrophilic inflammation",
author = "Bak, {Sang Myeon} and Park, {Soo Yeon} and Hur, {Gyu Young} and Lee, {Seung Heon} and Kim, {Je Hyeong} and Lee, {Sang Yeub} and Chol Shin and Shim, {Jae Jeong} and In, {Kwang Ho} and Kang, {Kyung Ho} and Yoo, {Se Hwa}",
year = "2003",
month = "1",
day = "1",
language = "English",
volume = "54",
pages = "80--90",
journal = "Tuberculosis and Respiratory Diseases",
issn = "1738-3536",
publisher = "The Korean Academy of Tuberculosis and Respiratory Diseases",
number = "1",

}

TY - JOUR

T1 - The role of neutrophils and epidermal growth factor receptors in lipopolysaccharide-induced mucus hypersecretion

AU - Bak, Sang Myeon

AU - Park, Soo Yeon

AU - Hur, Gyu Young

AU - Lee, Seung Heon

AU - Kim, Je Hyeong

AU - Lee, Sang Yeub

AU - Shin, Chol

AU - Shim, Jae Jeong

AU - In, Kwang Ho

AU - Kang, Kyung Ho

AU - Yoo, Se Hwa

PY - 2003/1/1

Y1 - 2003/1/1

N2 - Background: Goblet cell hyperplasia is a critical pathological feature in hypersecretory diseases of the airways. A bacterial infection of the lung is also known to induce inflammatory responses, which can lead to the overproduction of mucus. Recently, mucin synthesis in the airways has been reported to be regulated by neutrophilic inflammation-induced epidermal growth factor receptor (EGFR) expression and activation. In addition, it was reported that migration of the activated neutrophils is dependent on the matrix metalloproteinases (MMPs), especially MMP-9. In this study, bacterial lipopolysaccharide (LPS)-induced goblet cell hyperplasia and mucus hypersecretion by EGFR cascade, resulting from the MMPs-dependent neutrophilic inflammation were investigated in the rat airways. Methods: Pathogen-free Sprague-Dawley rats were studied in vivo. Various concentrations of LPS were instilled into the trachea in 300ℓ PBS (LPS group). Sterile PBS (300ℓ) was instilled into the trachea of the control animals (control group). The airways were examined on different days after instilling LPS. For an examination of the relationship between the LPS-induced goblet cell hyperplasia and MMPs, the animals were pretreated 3 days prior to the LPS instillation and daily thereafter with the matrix metalloproteinase inhibitor (MMPI; 20 mg/Kg/day of CMT-3; Collagenex Pharmaceuticals, USA). The neutrophilic infiltration was quantified as a number in five high power fields (HPF). The alcian blue/periodic acid-Schiff (AB/PAS) stain were performed for the mucus glycoconjugates and the immunohistochemical stains were performed for MUC5AC, EGFR and MMP-9. Their expressions were quantified by an image analysis program and were expressed by the percentage of the total bronchial epithelial area. Results: The instillation of LPS induced AB/PAS and MUC5AC staining in the airway epithelium in a time- and dose-dependent manner. Treatment with the MMPI prevented the LPS-induced goblet cell hyperplasia significantly. The instillation of LPS into the trachea induced also EGFR expression in the airway epithelium. The control airway epithelium contained few leukocytes, but the intratracheal instillation of LPS resulted in a neutrophilic recruitment. A pretreatment with MMPI prevented neutrophilic recruitment, EGFR expression, and goblet cell hyperplasia in the LPS-instilled airway epithelium. Conclusion: Matrix metalloproteinase is involved in LPS-induced mucus hypersecretion, resulting from a neutrophilic inflammation and EGFR cascade. These results suggest a potential therapeutic role of MMPI in the treatment of mucus hypersecretion that were associated with a bacterial infection of the airways.

AB - Background: Goblet cell hyperplasia is a critical pathological feature in hypersecretory diseases of the airways. A bacterial infection of the lung is also known to induce inflammatory responses, which can lead to the overproduction of mucus. Recently, mucin synthesis in the airways has been reported to be regulated by neutrophilic inflammation-induced epidermal growth factor receptor (EGFR) expression and activation. In addition, it was reported that migration of the activated neutrophils is dependent on the matrix metalloproteinases (MMPs), especially MMP-9. In this study, bacterial lipopolysaccharide (LPS)-induced goblet cell hyperplasia and mucus hypersecretion by EGFR cascade, resulting from the MMPs-dependent neutrophilic inflammation were investigated in the rat airways. Methods: Pathogen-free Sprague-Dawley rats were studied in vivo. Various concentrations of LPS were instilled into the trachea in 300ℓ PBS (LPS group). Sterile PBS (300ℓ) was instilled into the trachea of the control animals (control group). The airways were examined on different days after instilling LPS. For an examination of the relationship between the LPS-induced goblet cell hyperplasia and MMPs, the animals were pretreated 3 days prior to the LPS instillation and daily thereafter with the matrix metalloproteinase inhibitor (MMPI; 20 mg/Kg/day of CMT-3; Collagenex Pharmaceuticals, USA). The neutrophilic infiltration was quantified as a number in five high power fields (HPF). The alcian blue/periodic acid-Schiff (AB/PAS) stain were performed for the mucus glycoconjugates and the immunohistochemical stains were performed for MUC5AC, EGFR and MMP-9. Their expressions were quantified by an image analysis program and were expressed by the percentage of the total bronchial epithelial area. Results: The instillation of LPS induced AB/PAS and MUC5AC staining in the airway epithelium in a time- and dose-dependent manner. Treatment with the MMPI prevented the LPS-induced goblet cell hyperplasia significantly. The instillation of LPS into the trachea induced also EGFR expression in the airway epithelium. The control airway epithelium contained few leukocytes, but the intratracheal instillation of LPS resulted in a neutrophilic recruitment. A pretreatment with MMPI prevented neutrophilic recruitment, EGFR expression, and goblet cell hyperplasia in the LPS-instilled airway epithelium. Conclusion: Matrix metalloproteinase is involved in LPS-induced mucus hypersecretion, resulting from a neutrophilic inflammation and EGFR cascade. These results suggest a potential therapeutic role of MMPI in the treatment of mucus hypersecretion that were associated with a bacterial infection of the airways.

KW - Epidermal growth factor receptor

KW - Goblet cell hyperplasia

KW - Lipopolysaccharide

KW - Mucus hypersecretion

KW - Neutrophilic inflammation

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M3 - Article

VL - 54

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