A case of localized tracheobronchial relapsing polychondritis with positive matrilin-1 staining.

BACKGROUND: Relapsing polychondritis (RPC) is a rare progressive autoimmune disease characterized by inflammation in the cartilage of multiple organs. Tracheobronchial involvement appears in nearly half of RPC patients during the course of their disease and represents the main cause of death. Localized tracheobronchial RPC is much rarer, and the pathogenesis remains unclear. Matrilin-1 is a non-collagenous cartilage matrix protein and has been suggested to be a potent autoantigen that induces the airway disease of RPC in animal models. However, the expression of matrilin-1 in tracheobronchial tissue in human remains unclear. Therefore, we examined the expression of matrilin-1 in the tracheal and auricular tissues in a localized tracheobronchial RPC patient. CASE PRESENTATION: A 62-year-old man with systemic sclerosis presented with cough and dyspnea on exertion. The lung function test showed an expiratory flow limitation and chest computed tomography showed diffuse thickness from the trachea to the bronchiole. No other tests showed abnormal findings. To evaluate further, bronchoscopy was performed and endobronchial ultrasonography showed thickness in the fourth-marginal echo layer suggesting inflammation of the cartilage. However, the tracheal biopsy showed no specific findings. The subsequent surgical tracheal biopsies showed inflammatory cell infiltration with destruction of the cartilage. Neither auricular nor nasal deformity, except for a tracheobronchial lesion, was detected. Biopsy from the left auricular cartilage also did not show any inflammatory changes. Finally, we diagnosed the patient with localized tracheobronchial RPC. To address the hypothesis that autoimmunity against matrilin-1 is involved in the pathogenesis of localized tracheobronchial RPC, we evaluated the expression level of matrilin-1 in a tracheal and auricular specimen from this patient. Immunohistochemical staining with anti-matrilin-1 antibody showed matrilin-1 in the tracheal but not in the auricular cartilage. CONCLUSIONS: We first demonstrated the expression of matrilin-1 in tracheal but not in auricular cartilage in a localized tracheobronchial RPC patient. This result supports the possibility that matrilin-1 is involved in the pathogenesis of localized tracheobronchial RPC. However, this is only one case report and further observations will be needed to confirm this result.

Correction to: Oxidative stress enhances the expression of IL-33 in human airway epithelial cells.

Figure 2 of this original publication was incorrectly formatted. The updated Fig. 2 is published in this correction article [1].

The first case of multiple pulmonary granulomas with amyloid deposition in a dental technician; a rare manifestation as an occupational lung disease.

BACKGROUND: Occupational lung diseases, such as pneumoconiosis, are one of the health problems of dental workers that have been receiving increasing interest. Pulmonary amyloidosis is a heterogenous group of diseases, and can be classified into primary (idiopathic) and secondary (associated with various inflammatory diseases, hereditary, or neoplastic). To date, the development of pulmonary amyloidosis in dental workers has not been reported. CASE PRESENTATION: A 58-year-old Japanese female presented with chest discomfort and low-grade fever that has persisted for 2 months. She was a dental technician but did not regularly wear a dust mask in the workplace. Chest X ray and computed tomography revealed multiple well-defined nodules in both lungs and fluorodeoxyglucose (FDG)-positron emission tomography revealed abnormal FDG uptake in the same lesions with a maximal standardized uptake value (SUV [max]) of 5.6. We next performed thoracoscopic partial resection of the lesions in the right upper and middle lobes. The histological examination of the specimens revealed granuloma formation with foreign body-type giant cells and amyloid deposition that was confirmed by Congo red staining and direct fast scarlet (DFS) staining that produce apple-green birefringence under crossed polarized light. Because there were no other causes underlying the pulmonary amyloidosis, we performed electron probe X-ray microanalysis (EPMA) of the specimens and the result showed silica deposition in the lesions. Based on these results, we finally diagnosed the patient with pulmonary granulomas with amyloid deposition caused by chronic silica exposure. Afterward, her symptoms were improved and the disease has not progressed for 2 years since proper measures against additional occupational exposure were implemented. CONCLUSIONS: Our case presented three important clinical insights: First, occupational exposure to silica in a dental workplace could be associated with the development of amyloid deposition in lung. Second, EPMA was useful to reveal the etiology of amyloid deposition in the lungs. Last, proper protection against silica is important to prevent further progression of the disease. In conclusion, our case suggested that occupational exposure to silica should be considered when amyloid deposition of unknown etiology is found in the lungs of working or retired adults.

Oxidative stress enhances the expression of IL-33 in human airway epithelial cells.

BACKGROUND: Interleukin-33 (IL-33) is a cytokine belonging to the IL-1 family, and its possible involvement in the pathophysiology of COPD and viral-induced exacerbations has been demonstrated. IL-33 has been shown to be increased in the airway epithelial cells from COPD patients, but the regulating mechanism of IL-33 expression in airway epithelial cells remains largely unknown. In the current study, we examined whether oxidative stress, which participates in the pathogenesis of COPD, affects the expression of IL-33 in airway epithelial cells and also evaluated the effect during viral infection. METHODS: The involvement of oxidative stress in the expression of IL-33, and its signal pathway was examined after stimulation with hydrogen peroxide (H2O2), with or without stimulation by polyinosinic-polycytidylic acid [poly (I:C)], a synthetic analogue of dsRNA that mimics viral infection, or rhinovirus infection in NCI-H292 cells and primary human bronchial epithelial cells (HBECs). In addition, the effect of antioxidant, N-acetylcysteine (NAC) in the expression of IL-33 was compared between HBECs from healthy subjects and those from COPD patients. RESULTS: Treatment with H2O2 significantly potentiated IL-33 expression in NCI-H292 cells, and the potentiation was reversed by NAC treatment. Mitogen-activated protein kinase (MAPK) inhibitors, but not nuclear factor-kappa B inhibitors, also significantly decreased the H2O2-potentiated IL-33 expression. In addition, H2O2 significantly potentiated the poly (I:C)- or rhinovirus-stimulated IL-33 expression. In HBECs from healthy subjects, H2O2-potentiated IL-33 expression and its reversal by NAC was also confirmed. Under the condition without H2O2-stimulation, treatment with NAC significantly decreased the expression of IL-33 in HBECs from COPD patients, but not in those from healthy subjects. CONCLUSIONS: These results demonstrate that oxidative stress involves in the expression of IL-33 in airway epithelial cells via MAPK signal pathway and it augments IL-33 expression during viral infection. This mechanism may participate in the regulation of IL-33 expression in airway epithelial cells in COPD and the viral-induced exacerbations. Modulation of this pathway could become a therapeutic target for viral-induced exacerbations of COPD.

Production of reactive persulfide species in chronic obstructive pulmonary disease.

BACKGROUND: Oxidative stress is a major aetiological factor driving chronic obstructive pulmonary disease (COPD). Recently recognised as potent antioxidants, reactive persulfide and polysulfide species are biosynthesised by cystathionine ß-synthase and cystathionine γ-lyase. The production of reactive persulfide and polysulfide species in the lungs of patients with COPD remain unknown. OBJECTIVES: The aim of this study was to examine the production of reactive persulfides and polysulfides, such as glutathione persulfide (GSSH), cysteine persulfide (CysSSH) and glutathione trisulfide (GSSSH), in lung-resident cells and epithelial lining fluid (ELF) obtained from patients with mild to moderate COPD. METHODS: Lung tissues, primary lung cells, ELF and sputum were obtained. The amounts of reactive persulfides and polysulfides in the cells and ELF were measured by liquid chromatography-tandem mass spectrometry with ß-(4-hydroxyphenyl) ethyl iodoacetamide as a trapping agent for hydroper/polysulfides. The amounts of synthases in the lung tissues, sputum and primary cells were quantified. RESULTS: The amounts of GSSH, CysSSH and GSSSH were decreased in the lung cells and ELF from patients with COPD. The amounts of reactive persulfides and polysulfides in the lung cells had a positive correlation with the degree of airflow limitation. By contrast, the amounts of the synthases were increased in the lung tissues and sputum cells of patients with COPD. CONCLUSIONS: We have identified a decrease in reactive persulfide and polysulfide species in the lungs of patients with COPD. These data suggest that the newly detected antioxidants reactive persulfides and polysulfides could be associated with the redox balance in the lungs of patients with COPD.

Extracellular ATP is involved in dsRNA-induced MUC5AC production via P2Y2R in human airway epithelium.

BACKGROUND: In response to tissue damage or inflammation, adenosine-5'-triphosphate (ATP) is released into the extracellular compartment and has been demonstrated to augment inflammation via purinergic P2 receptors (P2Rs). Recently, ATP has been shown to be increased in the airways of COPD patients. In the present study, we examined the possible involvement of extracellular ATP in airway mucus hypersecretion during viral-induced COPD exacerbations. METHODS: The involvement of extracellular ATP in the release of a major airway mucin, MUC5AC, and its signal pathway was examined after stimulation with polyinosine-polycytidylic acid [poly(I:C)], a synthetic analog of dsRNA to mimic viral infection, and rhinovirus (RV) infection in NCI-H292 cells and differentiated airway epithelial cells from COPD patients. RESULTS: Treatment with poly(I:C) significantly increased the amount of extracellular ATP and induced MUC5AC release in NCI-H292 cells. Pre-treatment with a pannexin channel inhibitor, carbenoxolone (CBX), reduced the amount of extracellular ATP and suppressed MUC5AC release from poly(I:C)-treated cells. Pre-treatment with the P2R antagonist suramin significantly reduced the expression and release of MUC5AC. The inhibitory effects of CBX and suramin on the release of ATP and/or MUC5AC were replicated with RV infection. Pre-treatment with suramin also significantly reduced the expression and amount of extracellular EGFR ligands and the phosphorylation of EGFR and ERK in poly(I:C)-treated cells. In addition, pre-treatment with a P2Y2 receptor siRNA significantly suppressed the poly(I:C)-potentiated EGFR ligands and MUC5AC release. After poly(I:C) stimulation, the expression of MUC5AC in the differentiated cells from COPD patients was significantly higher than those from healthy subjects and the values of MUC5AC expression were inversely related with forced expiratory volume in 1 s (FEV1) % predicted. The inhibitory effects of CBX and suramin on poly(I:C)-potentiated MUC5AC expression were confirmed in differentiated airway epithelium from COPD patients. CONCLUSIONS: These results demonstrate that dsRNA induces the release of ATP via pannexin channel and that the extracellular ATP is involved in the expression and release of MUC5AC, mainly via P2Y2R, in an autocrine manner. Modulation of this pathway could be a therapeutic target for viral-induced mucus hypersecretion in COPD exacerbations.

Cigarette smoke augments MUC5AC production via the TLR3-EGFR pathway in airway epithelial cells.

BACKGROUND: Viral infections are a major cause of chronic obstructive pulmonary disease (COPD) exacerbations. Toll-like receptor 3 (TLR3) reacts with double-stranded RNA (dsRNA) and participates in the immune response after viral infection. In the present study, we examined whether cigarette smoke, which is involved in the pathogenesis of COPD, enhances mucin production via the TLR3-epidermal growth factor receptor (EGFR) pathway in airway epithelial cells. METHODS: We studied the effects of cigarette smoke extract (CSE) on signal transduction and the production of mucin 5AC (MUC5AC) in NCI-H292 cells and differentiated primary human bronchial epithelial cells stimulated with a synthetic dsRNA analogue, polyinosinic-polycytidylic acid [poly(I:C)], used as a TLR3 ligand. RESULTS: CSE significantly potentiated the production of MUC5AC in epithelial cells stimulated with poly(I:C). Antibodies to EGFR or EGFR ligands inhibited CSE-augmented MUC5AC release in poly(I:C)-treated cells. Treatment with poly(I:C) or CSE alone increased the phosphorylation of EGFR and extracellular signal-regulated kinase (ERK). However, after poly(I:C) stimulation, CSE did not enhance EGFR phosphorylation, but did augment ERK phosphorylation. EGFR inhibitors and an ERK inhibitor inhibited the augmented release of MUC5AC. In addition, treatment with N-acetylcysteine, an antioxidant, inhibited the CSE-augmented phosphorylation of ERK and MUC5AC. CONCLUSIONS: These data show that cigarette smoke increases TLR3-stimulated MUC5AC production in airway epithelial cells, mainly via ERK signaling. The effect might be mediated in part by oxidative stress. Modulation of this pathway might be a therapeutic target for viral-induced mucin overproduction in COPD exacerbation.

[Two cases of pulmonary aspergilosis, which deteriorated with generic itraconazole].

We experienced two cases of pulmonary aspergillosis, which deteriorated during treatment with generic itraconazole (ITCZ) because of low plasma concentration. One case was chronic pulmonary aspergillosis and the other was allergic bronchopulmonary aspergillosis (ABPA). Treatment of both cases was started with a brand-name-ITCZ, and changed to a generic ITCZ. Deterioration of pulmonary aspergillosis occurred after 8 months and 9 months from change to generic ITCZ respectively. In the first case, the ITCZ-plasma concentration was 46.9 ng/mL and of OH-ITCZ 96.5 ng/mL with generic ITCZ at the dose of 300 mg/day, but increased to 1,559.7 ng/mL and to 2,485.0 ng/mL with the brand-name-ITCZ 300 mg/day, respectively. In the second case, the ITCZ-plasma concentration was 27.2 ng/mL and of OH-ITCZ 20.1 ng/mL with 150 mg/day for generic ITCZ, but reached 857.3 ng/mL and to 1,144.2 ng/ml with the brand-name-ITCZ 300 mg/day, respectively. After treatment failure, the first case was changed to voriconazole, then brand-name-ITCZ 300 mg/day, and the second case to the brand-name-ITCZ 300 mg/day, with successful clinical course. Plasma concentrations of ITCZ can differ significantly depending on the patient or type of ITCZ. The ITCZ-plasma concentration should be controlled after changing from a brand-name-ITCZ to a generic ITCZ.

[Successful reintroduction of mesylate imatinib after pneumonitis in two patients with gastrointestinal stromal tumor (GIST)].

We report 2 cases of successful reintroduction of mesylate imatinib for gastrointestinal stromal tumor (GIST) after drug-induced pneumonitis. Both of them were women in the fifth decade who had been medicated by mesylate imatinib about for 5 months previously, and had been given a diagnosis of imatinib mesylate-induced pneumonitis. After only cessation of that drug, symptoms and shadows on chest X-ray film improved. However, we had to reintroduce the drug because of the growth of primary tumor, so we gave half the previous dose of imatinib mesylate, with low dose prednisone. There has been no recurrence of drug related pneumonitis and effective control of the primary tumor was obtained. The evidence acquired from our cases suggests that it may be possible to reintroduce imatinib mesylate carefully by adjusting the dose with low dose prednisone in a GIST patient, without causing recurrence of drug-induced pneumonitis.

[Case of severe streptococcus pyogenes pneumonia with streptococcus toxic shock syndrome].

A 30-year-old woman who had until recently been healthy, was transferred to our hospital by ambulance with complaints of dyspnea and pain in both lower limbs. She had 1-week history of sore throat, fever and cough. She had been to a neighboring clinic three days previously, and had been prescribed some medication for bronchitis, but her symptoms had not improved. By the time of admission, she was already in shock and had severe respiratory failure. Laboratory data showed renal dysfunction, disseminated intravascular coagulation, CPK elevation and severe metabolic acidosis. Chest x-ray and CT films revealed consolidation of the entire right lung field. The patient was quickly intubated and we began mechanical ventilation. We immediately initiated broad-spectrum antibiotics, immunogloblin, dopamine hydrochloride and gabexate mesilate, but she died 7 hours later. From cultures of blood and sputum taken from the patient, Streptococcus pyogenes was isolated. On the basis of these clinical and bacteriological findings, we confirmed a diagnosis of pneumonia and toxic shock syndrome caused by Streptococcus pyogenes (STSS). Serologically her M protein was serotyped as M1, and with regard to Streptococcal pyrogenic exotoxin genes were identified as speA and speB. These serological findings were consistent with the most frequent type that causes STSS. In spite of the uncommon cause of community-acquired pneumonia, Streptococcus pyogenes can potentially affect healthy individuals. The pneumonia can be complicated with STSS and so the clinical course may be severe and fulminant. The evidence acquired from this case suggests that in the event of severe pneumonia with shock, we should be aware that this may represent the presence of Streptococcus pyogenes and/or toxic shock syndrome.