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 300microliter PBS (LPS group). Sterile PBS (300microliter) 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.
Animals ; Bacterial Infections ; Coloring Agents ; Epidermal Growth Factor* ; Epithelium ; Glycoconjugates ; Goblet Cells ; Hyperplasia ; Inflammation ; Leukocytes ; Lung ; Matrix Metalloproteinases ; MMPI ; Mucins ; Mucus* ; Neutrophils* ; Rats ; Rats, Sprague-Dawley ; Receptor, Epidermal Growth Factor* ; Trachea

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 300microliter PBS (LPS group). Sterile PBS (300microliter) 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.
Animals ; Bacterial Infections ; Coloring Agents ; Epidermal Growth Factor* ; Epithelium ; Glycoconjugates ; Goblet Cells ; Hyperplasia ; Inflammation ; Leukocytes ; Lung ; Matrix Metalloproteinases ; MMPI ; Mucins ; Mucus* ; Neutrophils* ; Rats ; Rats, Sprague-Dawley ; Receptor, Epidermal Growth Factor* ; Trachea

A 38-year-old woman presented with facial edema with neck vein engorgement for about 45 days. Chest roentgenography showed bulging soft tissue opacities in the right superoanterior mediastinum and a lobulated intraluminal mass was noted in the superior vena cava on the venacavogram. The superior vena cava was incised and the tumor located from the junction of the superior vena cava and internal jugular vein to the right atrial inlet was excised. Grossly, the tumor was myxoid or gelatinous in appearance. A combination of microscopic and immunohistochemical features showed myxoid leiomyosarcoma arising from the wall of the superior vena cava.
Adult ; Bays ; Edema ; Female ; Gelatin ; Humans ; Jugular Veins ; Leiomyosarcoma* ; Mediastinum ; Neck ; Radiography ; Superior Vena Cava Syndrome* ; Thorax ; Veins ; Vena Cava, Superior*

Cryoglobulinemia is the presence of globulins in the serum that precipitate on exposure to cold temperatures (cryoglobulins). Pulmonary complications of cryoglobulinemia include interstial infiltration, impaired gas exchange, small airway disease and pleurisy. Only one other acute respiratory distress syndrome(ARDS) case has been described in patients with cryoglobulinemia. A 55-years old man was admitted with dyspnea. He had been diagnosed as being a hepatitis B virus antigen carrier 15 years age. On the first admission, chest radiography showed a bilateral pleural effusion and a patchy infiltration on both lungs. On protein-and immuno-electrophoresis, cryoglobulinemia was confirmed. The patient was treated with corticosteroid and plasmapheresis. Forty-five days after the diagnosis, the patient complained of progressive dyspnea and showed a diffuse bilateral pulmonary infiltration on chest radiography. Despite intensive care with mechanical ventilation, the patient died as consequence of hypoxemia and multiple systemic organ failure. On a pathologic examination of the postmortem lung biopsy, multiple necrotizing vasculitis and increased infiltration of the lymphocytes and monocytes were observed. In conclusion, ARDS developed as a result of pulmonary hemorrhage due to cryoglobulinemia-associated vasculitis.
Anoxia ; Biopsy ; Cold Temperature ; Cryoglobulinemia ; Diagnosis ; Dyspnea ; Globulins ; Hemorrhage ; Hepatitis B virus ; Humans ; Critical Care ; Lung ; Lymphocytes ; Monocytes ; Plasmapheresis ; Pleural Effusion ; Pleurisy ; Radiography ; Respiration, Artificial ; Respiratory Distress Syndrome, Adult* ; Thorax ; Vasculitis

Although anti-aging activities of melatonin, a hormone secreted by the pineal gland, have been reported in senescence-accelerated mouse models and several types of cells, its impact and mechanism on the senescence of human dental pulp cells (HDPCs) remains unknown. In this study, we examined the impact of melatonin on cellular premature senescence of HDPCs. Here, we found that melatonin markedly inhibited senescent characteristics of HDPCs after exposure to hydrogen peroxide (H₂O₂), including the increase in senescence-associated β-galactosidase (SA-β-gal)-positive HDPCs and the upregulation of p21 protein, an indicator for senescence. In addition, as melatonin attenuated H₂O₂-stimulated phosphorylation of c-Jun N-terminal kinase (JNK), while selective inhibition of JNK activity with SP600125 significantly attenuated H₂O₂-induced increase in SA-beta-gal activity. Results reveal that melatonin antagonizes premature senescence of HDPCs via JNK pathway. Thus, melatonin may have therapeutic potential to prevent stress-induced premature senescence, possibly correlated with development of dental pulp diseases, and to maintain oral health across the life span.
Aging* ; Animals ; Dental Pulp Diseases ; Dental Pulp* ; Humans* ; Hydrogen Peroxide ; JNK Mitogen-Activated Protein Kinases ; MAP Kinase Signaling System ; Melatonin* ; Mice ; Oral Health ; Phosphorylation ; Pineal Gland ; Up-Regulation

Cholestatic liver cirrhosis (CLC) eventually proceeds to end-stage liver failure by mediating overwhelming deposition of collagen, which is produced by activated interstitial myofibroblasts. Although the beneficial effects of Rhus verniciflua Stokes (RVS) on various diseases are well-known, its therapeutic effect and possible underlying mechanism on interstitial fibrosis associated with CLC are not elucidated. This study was designed to assess the protective effects of RVS and its possible underlying mechanisms in rat models of CLC established by bile duct ligation (BDL). We demonstrated that BDL markedly elevated the serological parameters such as aspartate aminotransferase, alanine transaminase, total bilirubin, and direct bilirubin, all of which were significantly attenuated by the daily uptake of RVS (2 mg/kg/day) for 28 days (14 days before and after operation) via intragastric route. We observed that BDL drastically induced the deterioration of liver histoarchitecture and excessive deposition of extracellular matrix (ECM), both of which were significantly attenuated by RVS. In addition, we revealed that RVS inhibited BDL-induced proliferation and activation of interstitial myofibroblasts, a highly suggestive cell type for ECM production, as shown by immunohistochemical and semi-quantitative detection of α-smooth muscle actin and vimentin. Finally, we demonstrated that the anti-fibrotic effect of RVS was associated with the inactivation of Smad3, the key downstream target of a major fibrogenic cytokine, i.e., transforming growth factor β (TGF-β). Simultaneously, we also found that RVS reciprocally increased the expression of Smad7, a negative regulatory protein of the TGF-β/Smad3 pathway. Taken together, these results suggested that RVS has a therapeutic effect on CLC, and these effects are, at least partly, due to the inhibition of liver fibrosis by the downregulation of Smad3 and upregulation of Smad7.
Actins ; Alanine Transaminase ; Aspartate Aminotransferases ; Bile Ducts ; Bilirubin ; Collagen ; Down-Regulation* ; Extracellular Matrix ; Fibrosis* ; Ligation ; Liver Cirrhosis ; Liver Failure ; Liver* ; Models, Animal ; Myofibroblasts ; Negotiating ; Rhus* ; Transforming Growth Factors ; Up-Regulation* ; Vimentin