Novel roles for nasal epithelium in the pathogenesis of chronic rhinosinusitis with nasal polyps.

BACKGROUND: Airway epithelial cells have a well-accepted role in the regulation of local inflammatory processes in allergic and innate defence responses. However, their role the pathophysiology of chronic rhinosinusitis with nasal polyps (CRSwNP) is unclear. The objective was to investigate whether potential differences in the mRNA expression profile of nasal epithelia from healthy individuals and from CRSwNP patients would shed new light on disease mechanisms. METHODS: Primary epithelial cells from nasal polyps of 24 affected individuals and from middle turbinates of 9 healthy controls were obtained using magnetic beat assisted isolation and were used for expression profiling using the Human Genome U133 Plus 2.0 Genechip Array. RESULTS: Multiple gene probes corresponding to 27 genes showed an aberrant expression profile in polyp epithelial cells compared to healthy controls. Most of these genes are linked to pathogenic mechanisms seen in neoplasm formation, including changes in cell-cell adhesion, metabolic processes, cell cycle control, and differentiation. Remarkably, our data additionally suggest a role for maternally expressed genes in the pathogenesis of CRSwNP and reveal two distinct states of polyp epithelium that could not be linked to the presence or absence of atopy in patients or to the level of eosinophilia or neutrophilia of the polyp. CONCLUSIONS: Our data suggest new roles for nasal epithelium in the pathogenesis of CRSwNP.

Local and systemic proteolytic responses in chronic rhinosinusitis with nasal polyposis and asthma.

BACKGROUND: Chronic rhinosinusitis with nasal polyposis (CRSwNP) and asthma coexist frequently and share similar features of inflammation and remodeling. Remodeling has become an important concept in the pathophysiology of asthma and CRSwNP. It happens early in the development of these diseases and is relatively resistant to treatments. The key enzymes responsible for remodeling are matrix metalloproteinases (MMPs). In this study we examined whether asthma and CRSwNP share similar MMP profiles. METHODS: Nasal secretion and serum specimens of controls (19 subjects) and patients with asthma (12), CRSwNP (39), or both (16) were collected between December 2007 and May 2009. Groups were divided into 2 subgroups according to atopy. MMP-7, MMP-9, MMP-13, tissue inhibitors of metalloproteinases (TIMPs), TIMP-1 and TIMP-2, myeloperoxidase (MPO), and human neutrophil elastase (HNE) were measured using enzyme-linked immunosorbent assay (ELISA), and MMP-8 was determined using immunofluorometric assay. High-sensitivity C-reactive protein (hs-CRP) was measured to estimate systemic involvement. RESULTS: Patients with asthma, CRSwNP, or both exhibited lower MMP-9, MMP-9/TIMP-1, MMP-9/TIMP-2, and MPO in nasal secretions (p < 0.05 in CRSwNP) and higher MMP-9, MMP-9/TIMP-1, MMP-9/TIMP-2, and HNE in serum (p < 0.05 in all groups) compared to controls, whereas no difference in MMP-7, MMP-13, TIMP-1, and TIMP-2 were detected. Atopy increased nasal MMP-9 and MPO expression. hs-CRP was higher in patients with CRSwNP and asthma compared to controls. CONCLUSION: Our findings suggest shared pathomechanisms behind asthma and CRSwNP. Contrasting local vs systemic results reflect a different ability of healthy mucosa to react to exogenous stimuli, possibly indicating a protective function of MMP-9 and possibly also MMP-8 in the airways.

Role of matrix metalloproteinases in chronic rhinosinusitis.

PURPOSE OF REVIEW: In this review, we discuss the role of matrix metalloproteinases and the potential therapeutic inhibition of metalloproteinases in chronic rhinosinusitis. Metalloproteinases control tissue remodelling along with several other physiologic processes. Failures may cause extracellular matrix deposition and sustained inflammation, which are common features in chronic rhinosinusitis. RECENT FINDINGS: Metalloproteinases are rarely studied in chronic rhinosinusitis. Upregulation of certain metalloproteinases (gelatinases, collagenases and matrilysin) is described in the literature. The results are partly controversial, suggesting that metalloproteinases are implicated in the destructive processes in the disease pathogenesis, but also demonstrate that they may exert an anti-inflammatory function in chronic rhinosinusitis. The imbalance between metalloproteinases and the tissue inhibitor of metalloproteinases is proposed to be crucial in the extracellular matrix deposition in asthma, and it may also lead to pathologic tissue remodelling in chronic rhinosinusitis. SUMMARY: Metalloproteinases are implicated in the chronic respiratory-tract diseases, but little is known about their detailed functions in disease pathogenesis. Metalloproteinases may serve as tools in evaluating prognosis and provide a target for novel therapies, highlighting the need for better understanding of metalloproteinase functions in chronic rhinosinusitis.

Negative impact of Aspergillus galactomannan and DNA detection in the diagnosis of fungal rhinosinusitis.

A proportion of patients with chronic rhinosinusitis, especially if nasal polyps are present, have a diagnosis of fungal rhinosinusitis. The diagnosis is difficult to establish because the symptoms and clinical and radiological signs are non-specific. Also current diagnostic methods, i.e. histology, fungal staining and culture, are insensitive. The performance of the Aspergillus galactomannan (GM) ELISA and real-time PCR for Aspergillus fumigatus mitochondrial DNA was evaluated for the detection of Aspergillus in sinus mucus samples from 25 patients with chronic rhinosinusitis with nasal polyposis. The results were compared with those from nasal lavage fluid from 19 healthy volunteers. Seven patients (28 %) were diagnosed as having fungal rhinosinusitis according to the presence of filaments in histology or direct microscopy using Calcofluor white. All fungal rhinosinusitis patients were negative in the GM ELISA. GM ELISA was positive in five patients whose samples were negative using conventional methods and A. fumigatus PCR. Two out of seven patients with fungal rhinosinusitis were positive by A. fumigatus PCR: one also had a positive A. fumigatus culture, and one had hyphae consistent with Aspergillus in histology. One additional patient had a weak positive PCR result, but other fungal tests were negative. In control subjects, the GM ELISA was positive in 21 %, whereas direct microscopy, culture and A. fumigatus PCR were negative in all samples. Direct microscopy and culture together with histology remain pivotal in defining fungal rhinosinusitis diagnosis. A. fumigatus PCR may have additional value in allowing the diagnosis to be made sooner, whereas the GM ELISA is not reliable in diagnosing Aspergillus infection of the paranasal sinuses.

Metalloproteinase function in chronic rhinosinusitis with nasal polyposis.

OBJECTIVES: Chronic rhinosinusitis with nasal polyposis (CRSwNP) and asthma share characteristic inflammatory features and histopathologic findings of airway remodeling. Remodeling, which is controlled by matrix metalloproteinases (MMP), is a key event in the pathogenesis of asthma. The MMP functions have rarely been evaluated in CRSwNP. STUDY DESIGN: Prospective and in vivo. METHODS: MMP-7, MMP-8, MMP-9, and tissue inhibitor of metalloproteinase (TIMP)-1 concentrations were analyzed by enzyme-linked immunosorbent assay and their molecular forms by Western immunoblotting and gelatin zymography in 24 patients operated on for CRSwNP and in nasal lavages from 19 healthy controls. MMP function, protective or destructive, was evaluated by comparing MMP/TIMP-1 levels with the disease activity, estimated by tissue eosinophilia and a need for re-operations. RESULTS: Significantly increased levels of MMP-8/TIMP-1 and MMP-9/TIMP-1 were found in patients without tissue eosinophilia relative to eosinophil-positive CRSwNP patients and controls, as well as in patients who did not require re-operation in comparison with re-operated patients. In eosinophil-positive and re-operated patients, these parameters were within the same range than in controls. CONCLUSIONS: Proteolytic spectrum is different in eosinophilic and noneosinophilic CRSwNP, suggesting a new mechanism for eosinophil accumulation in the disease pathogenesis. Enhanced MMP-8 and MMP-9 expression was associated with a better prognosis/clinical outcome, and thus these results may represent a synergic, protective role of MMP-8 and MMP-9 in host response in CRSwNP. Because synthetic MMP inhibitors, capable of equilibrating the unfavorable MMP/TIMP-ratio, may be of potential therapeutic value in chronic respiratory tract diseases, the MMP functions in inflammatory conditions need to be carefully established.

Microbiology of chronic hyperplastic sinusitis.

BACKGROUND: Patients with chronic hyperplastic sinusitis (CHS) form a heterogeneous group with similar symptoms and similar treatment despite of possible different mechanisms behind the disease. In the present study we focused on the microbiological findings in CHS and compared these results to the patient history in order to find out a possible explanation for the aetiology and chronicity of CHS. METHODS: In 30 patients the sinus mucus was collected under endoscopic sinus surgery. Samples from 20 healthy volunteers were collected by nasal lavage. Eosinophil staining, bacterial culturing and fungal staining and culturing were done. Histological samples were obtained from all patients. RESULTS: Bacterial cultures were positive in 93% of the patients compared to 70% in controls. Staphylococcus aureus and coagulase-negative Staphylococci were the two most common findings in both groups. A total of seven patients had positive fungal finding. The only fungal genus found was Aspergillus. In the control group no samples were positive for fungi. CONCLUSIONS: Microbiological findings do not seem to explain the chronic course of CHS, but fungi may play some part in the pathophysiology of the disease. These results may be more a reflection of a change in the environment in the paranasal sinuses and a change in normal flora than the actual cause of CHS.