Biomedical subjects

E Escudier

Publications and source records attributed to E Escudier.

At least 19 recordsLinked to original sources

PubMed2006

Transforming growth factor-beta1 increases airway wound repair via MMP-2 upregulation: a new pathway for epithelial wound repair?

In vivo, transforming growth factor (TGF)-beta1 and matrix metalloproteinases (MMPs) present at the site of airway injury are thought to contribute to epithelial wound repair. As TGF-beta1 can modulate MMP expression and MMPs play an important role in wound repair, we hypothesized that TGF-beta1 may enhance airway epithelial repair via MMPs secreted by epithelial cells. We evaluated the in vitro influence of TGF-beta1 on wound repair in human airway epithelial cells cultured under conditions allowing differentiation. The results showed that TGF-beta1 accelerated in vitro airway wound repair, whereas MMP inhibitors prevented this acceleration. In parallel, we examined the effect of TGF-beta1 on the expression of MMP-2 and MMP-9. TGF-beta1 induced a dramatic increase of MMP-2 expression with an increased steady-state level of MMP-2 mRNA, contrasting with a slight increase in MMP-9 expression. To confirm the role of MMP-2, we subsequently evaluated the effect of MMP-2 on in vitro airway wound repair and demonstrated that the addition of MMP-2 reproduced the acceleration of wound repair induced by TGF-beta1. These results strongly suggest that TGF-beta1 increases in vitro airway wound repair via MMP-2 upregulation. It also raises the issue of a different in vivo biological role of MMP-2 and MMP-9 depending on the cytokine microenvironment.

Gelatinases↗

PubMed2006

Matrix metalloproteinase-2 and -9 expression in sinonasal inverted papilloma.

STATEMENT OF PROBLEM: Inverted papilloma (IP) is a proliferative lesion of the epithelium lining the sinonasal tract, characterized by marked propensity for recurrence and association with carcinoma. To determine a putative role of matrix metalloproteinase-2 (MMP-2) and MMP-9 in the establishment of IP, their expression was studied in IP. METHODS: Archived surgical specimens from 15 IPs were studied using immunohistochemistry and compared to 12 nasal polyps (NP), a model of chronic respiratory mucosal inflammation, and to 6 control nasal mucosa (CM) samples obtained from snorers during turbinectomy. Within IP, MMP-2 and -9 expression was compared between tumoral areas with hyperplastic epithelium and non tumoral areas with nonhyperplastic epithelium. RESULTS: In IP, MMP-2 and MMP-9 epithelial expression was not different compared to CM and NP. MMP-9 expression in submucosal inflammatory cells was not different between IP and CM or NP. However, within IP, a significantly increased number of MMP-9 positive inflammatory cells in the lamina propria adjacent to the hyperplastic epithelium was observed compared to the lamina propria adjacent to nonhyperplastic epithelium. CONCLUSION: Our findings suggest that MMP 9 expressing inflammatory cells may be involved in the pathophysiology of IP.

Case-Control Studies↗

PubMed2005

RPGR is mutated in patients with a complex X linked phenotype combining primary ciliary dyskinesia and retinitis pigmentosa.

INTRODUCTION: Primary ciliary dyskinesia (PCD) is a rare disease classically transmitted as an autosomal recessive trait and characterised by recurrent airway infections due to abnormal ciliary structure and function. To date, only two autosomal genes, DNAI1 and DNAH5 encoding axonemal dynein chains, have been shown to cause PCD with defective outer dynein arms. Here, we investigated one non-consanguineous family in which a woman with retinitis pigmentosa (RP) gave birth to two boys with a complex phenotype combining PCD, discovered in early childhood and characterised by partial dynein arm defects, and RP that occurred secondarily. The family history prompted us to search for an X linked gene that could account for both conditions. RESULTS: We found perfect segregation of the disease phenotype with RP3 associated markers (Xp21.1). Analysis of the retinitis pigmentosa GTPase regulator gene (RPGR) located at this locus revealed a mutation (631_IVS6+9del) in the two boys and their mother. As shown by study of RPGR transcripts expressed in nasal epithelial cells, this intragenic deletion, which leads to activation of a cryptic donor splice site, predicts a severely truncated protein. CONCLUSION: These data provide the first clear demonstration of X linked transmission of PCD. This unusual mode of inheritance of PCD in patients with particular phenotypic features (that is, partial dynein arm defects and association with RP), which should modify the current management of families affected by PCD or RP, unveils the importance of RPGR in the proper development of both respiratory ciliary structures and connecting cilia of photoreceptors.

Adolescent↗

PubMed2004

[Nasal ciliary investigations for the diagnosis of primary ciliary dyskinesia in children].

Primary ciliary dyskinesia (PCD) is an autosomal recessive disorder, characterized by chronic infections of the upper and lower airways, associated in 50% of cases with situs inversus, therefore, corresponding to Kartagener's syndrome. PCD is suspected on clinical features, including bronchitis, rhinosinusitis and chronic otitis media beginning in early childhood. The recurring infections eventually lead to bronchiectasis. The clinical features of PCD have been ascribed to primary defects in cilia, which lead to impairment of mucociliary clearance. Ciliary investigations looking for abnormalities in ciliary motion and ultrastructure can be easily performed at nasal level. Quantitative ultrastructural study of cilia is performed in cases of abnormal ciliary motion and/or clinical symptoms highly suggestive of PCD. In PCD, all or most of the cilia are abnormal, all bearing the same ultrastructural defects, mainly concerning dynein arms. In older children, the detection of a very low nasal NO output could also be useful for the diagnosis of PCD. As soon as the ciliary investigations are easy to perform at the nasal level, they could help for a better detection of PCD. This strategy could be especially useful in cases of atypical presentations, which are underestimated as a cause of recurrent airway infections. Diagnosis of PCD is important in order to prevent the development of bronchiectasis and to avoid any unnecessary procedure.

Age Factors↗

PubMed2004

[Molecular basis of the primary ciliary dyskinesias].

INTRODUCTION: The primary ciliary dyskinesias (PCD) are rare diseases characterised by infection of the airways due to impaired muco-ciliary clearance. Half the patients have situs inversus making up Kartagener's syndrome. STATE OF THE ART: Primary cilia play a role in development. In the adult ciliated cells occur mainly in the airways and the genital tract. The axoneme, the internal structure of the cilia, is made up of a central pair of microtubules surrounded by peripheral doublets carrying the inner and outer dynein arms. These multiprotein complexes are composed of chains of dynein whose ATPase activity is the basis of ciliary movement. Structural and functional abnormalities of the respiratory ciliated cells are the cause of PCD, diseases that are heterogeneous at both the genetic and ultrastructural levels. PERSPECTIVES: There are more than two hundred axonemal proteins. The synthesis and assembly of these proteins are controlled by transcription factors and intraflagellar transport molecules respectively. The genes that code for these proteins are as numerous as candidate genes for PCD. CONCLUSIONS: To date only two dynein genes, DNA11 and DNAH5, have been implicated and only in individuals suffering from PCD with absence of outer dynein arms.

Animals↗

PubMed2004

Atypical sinusitis in adults must lead to looking for cystic fibrosis and primary ciliary dyskinesia.

UNLABELLED: HYPOTHESES/OBJECTIVES:: In adults, purulent pansinusitis or nasal polyposis starting early in life or that is permanently infected or associated either with chronic bronchial infection, infertility, or situs inversus are uncommon. In these atypical cases of chronic sinusitis (ACS), a primary dysfunction of the mucociliary clearance can be suspected. Adult patients with ACS were therefore investigated to detect primary ciliary dyskinesia (PCD) or cystic fibrosis (CF). STUDY DESIGN: Open, prospective study. PATIENTS AND METHODS: Forty-two patients with ACS were investigated with ciliary beat frequency and ultrastructure analysis in nasal cells and cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation analysis in blood leukocytes. RESULTS: The diagnosis of PCD was confirmed in seven (17%) patients. At least one CFTR gene mutation was detected in 16 (38%) patients. The diagnosis of CF was suggested in three (7%) compound heterozygous patients. Another 13 (31%) patients were heterozygous for a CFTR gene mutation or a complex allele. Comparison of clinical features of ACS showed that only a family history of chronic sinusitis (P <.01) or chronic bronchitis (P <.02) and the presence of diffuse bronchiectasis (P <.0001) or serous otitis media (P <.0001) were significantly more frequent in PCD patients than in patients carrying CFTR gene mutations or those without PCD or CFTR gene mutations. CONCLUSIONS: ACS should be considered a remarkable entity in which congenital abnormalities of epithelial cells are frequently detected (55% of patients). The higher frequency of mutations in ACS patients compared with the general population suggests that heterozygoty for CFTR gene mutation could be a sinusitis-causing status.

Adult↗

PubMed2002

Aspergillus fumigatus causes in vitro electrophysiological and morphological modifications in human nasal epithelial cells.

The role of the airway epithelium in the development of invasive aspergillosis in immunocompromised hosts has rarely been studied although patients at risk for this infection frequently have epithelial damage. We developed an in vitro model of primary culture of human nasal epithelial cells (HNEC) in air-liquid interface, which allows epithelial cell differentiation and mimics in vivo airway epithelium. We subsequently tested 7-day and 24-hour Aspergillus fumigatus filtrates on the apical side of HNEC to know whether A. fumigatus, the main species responsible for invasive aspergillosis, produces specific damage to the epithelial cells. The results were compared with those obtained with non-pathogenic filamentous fungi. Seven-day culture filtrates of A. fumigatus and Penicillium chrysogenum induced electrophysiological modifications whatever the fungus tested. In contrast, only 24-hour A. fumigatus filtrates induced a specific decrease in transepithelial resistance, hyperpolarization of the epithelium, and cytoplasmic vacuolization of HNEC compared with both A. niger and Penicillium chrysogenum. The inhibition of the A. fumigatus effects with amiloride suggests that the 24-hour fungal filtrate acts through sodium channels of HNEC. These early modifications of the epithelial cells could facilitate colonization of the airways by A. fumigatus. To know whether the molecules involved are specific to A. fumigatus or simply produced more rapidly than by other filamentous fungi warrants further investigation. In this perspective, the primary culture of HNEC represents a suitable model to study the interactions between airway epithelial cells and A. fumigatus.

Amiloride↗

PubMed2001

Increased expression of matrix metalloproteinase-9 in nasal polyps.

To investigate the role of gelatinases in nasal polyposis, a common and disabling airway disease characterized by chronic inflammation and tissue remodelling, matrix metalloproteinase-2 (MMP-2) and MMP-9 expression was investigated in the nasal polyps (NP) of 24 patients undergoing ethmoidectomy and compared with 15 control nasal mucosal (CM) samples obtained from snorers during turbinectomy. Tissue samples were either frozen for enzymatic analysis or paraffin wax-embedded for immunohistochemistry. Zymography and quantitative image analysis showed that MMP-9 active forms were significantly increased (p<0.05) in NPs compared to CM (44 +/- 40 versus 13 +/- 19x10(3) AU/10 microg protein), while MMP-2 expression was similar in both tissues. Concomitant studies of gelatinase immunoexpression showed that MMP-9 expression was enhanced (4- to 16-fold) in surface epithelium, glands (p<0.05), and submucosal inflammatory cells (p<0.05). In addition, MMP-9 positivity was markedly increased in endothelial cells (p<0.01). In situ zymography demonstrated marked gelatinolytic activity, consistent with the immunolocalization of MMP-2 and MMP-9. These results suggest up-regulation of active MMP-9 in the glands and vessels characteristic of NPs. It is concluded that MMP-9 may play a role in the upper airway remodelling observed during nasal polyposis.

Adult↗

PubMed2001

Efficacy and tolerance of intranasal insulin administered during 4 months in severely hyperglycaemic Type 2 diabetic patients with oral drug failure: a cross-over study.

AIMS: We have evaluated the local tolerance and the metabolic efficacy of a lyophilized nasal insulin preparation in 10 severely hyperglycaemic Type 2 diabetic patients. METHODS: The study included two 4-month randomized periods: (A) three preprandial doses of nasal insulin secondarily combined with one evening subcutaneous NPH if the desired glycaemic control was not achieved; (B) two NPH injections daily. We assessed: (i) diabetes control on monthly HbA1c levels and occurrence of hypoglycaemic events; (ii) local tolerance on clinical symptoms, rhinoscopy, nasal muco-ciliary clearance and nasal biopsies; (iii) insulin absorption at months 0 and 4. RESULTS: One patient was withdrawn because of cough and dizziness after each nasal application. HbA1c was not significantly different at month 4 (9.4 +/- 0.5% vs. 8.8 +/- 0.2%, A vs. B). Blood glucose control remained only fair in the majority of our patients. Nasal insulin was able to replace the daytime fraction of the subcutaneous insulin with a 18% efficacy. Side-effects included transient nasal hyperactivity (pruritus, sneezing and rhinorrhoea) and chronic persistence of nasal crusts. Plasma insulin profiles were not significantly different between months 0 and 4. CONCLUSIONS: The utilization of nasal insulin (with or without NPH) was associated with similar diabetes control compared with NPH twice daily. Nasal insulin alone was able to achieve an adequate glycaemic control in three of the 10 patients.

Administration, Intranasal↗

PubMed2001

Radiofrequency is a safe and effective treatment of turbinate hypertrophy.

OBJECTIVE: To evaluate the safety and efficacy of radiofrequency for reduction of inferior turbinate volume. STUDY DESIGN: Prospective before-and-after trial. METHODS: Fourteen patients complaining of chronic nasal obstruction and failing to respond to medical treatment were prospectively enrolled. All patients presented with inferior turbinate hypertrophy and no septal deformity. Radiofrequency inferior turbinate tissue reduction with three punctures in each turbinate (mean energy/puncture: 342 +/- 36 J, mean duration: 69 +/- 17 s, plateau tissue temperature: 75 +/- 6.4 degrees C). Patients were evaluated before and on days 3, 7, and 60 after intervention. RESULTS: No postoperative pain or complications were reported. Evaluation of nasal obstruction, quantified by visual analogue scale, showed a significant decrease of day time and nighttime obstruction after surgery. Acoustic rhinometry measurements showed that turbinate hypertrophy was significantly reduced in the sitting and supine positions on day 60 after surgery. Saccharin transit times decreased significantly on day 60 compared with preoperative measurements. Ciliary beat frequency, measured in vitro in nasal epithelial cells sampled from the inferior turbinate by brushing, was not significantly different before surgery and on day 60 after surgery. In the same samples, ciliated cells were the most abundant epithelial cell type before and after surgery, although in five cases, moderate numbers of squamous cells were detected on either day 7 or day 60 after surgery. CONCLUSION: Radiofrequency is a safe surgical procedure capable of reducing turbinate volume without altering the nasal mucosa, and causing minimal discomfort for the patient.

Catheter Ablation↗

PubMed2001

Evaluation of basement membrane degradation during TNF-alpha-induced increase in epithelial permeability.

We evaluated whether tumor necrosis factor (TNF)-alpha induces an increase in permeability of an alveolar epithelial monolayer via gelatinase secretion and basement membrane degradation. Gelatinase secretion and epithelial permeability to radiolabeled albumin under unstimulated and TNF-alpha-stimulated conditions of an A549 human epithelial cell line were evaluated in vitro. TNF-alpha induced both upregulation of a 92-kDa gelatinolytic activity (pro form in cell supernatant and activated form in extracellular matrix) and an increase in the epithelial permeability coefficient compared with the unstimulated condition (control: 1.34 +/- 0.04 x 10(-6) cm/s; 1 microg/ml TNF-alpha: 1.47 +/- 0.05 x 10(-6) cm/s, P < 0.05). The permeability increase in the TNF-alpha-stimulated condition involved both paracellular permeability, with gap formation visualized by actin cytoskeleton staining, and basement membrane permeability, with an increase in the basement membrane permeability coefficient (determined after cell removal; control: 2.58 +/- 0.07 x 10(-6) cm/s; 1 microg/ml TNF-alpha: 2.82 +/- 0.02.10(-6) x cm/s, P < 0.05). Because addition of gelatinase inhibitors [tissue inhibitor of metalloproteinase (TIMP)-1 or BB-3103] to cell supernatants failed to inhibit the permeability increase, the gelatinase-inhibitor balance in the cellular microenvironment was further evaluated by cell culture on a radiolabeled collagen matrix. In the unstimulated condition, spontaneous collagenolytic activity inhibited by addition to the matrix of 1 microg/ml TIMP-1 or 10(-6) M BB-3103 was found. TNF-alpha failed to increase this collagenolytic activity because it was associated with dose-dependent upregulation of TIMP-1 secretion by alveolar epithelial cells. In conclusion, induction by TNF-alpha of upregulation of both the 92-kDa gelatinase and its inhibitor TIMP-1 results in maintenance of the gelatinase-inhibitor balance, indicating that basement membrane degradation does not mediate the TNF-alpha-induced increase in alveolar epithelial monolayer permeability.

Basement Membrane↗

PubMed2001

Abnormal central complex is a marker of severity in the presence of partial ciliary defect.

BACKGROUND: Ciliary ultrastructural defects with total lack of dynein arms (DA) cause abnormal mucociliary function leading to the chronic infections observed in primary ciliary dyskinesia. The role of partial ciliary ultrastructural defects, especially those involving the central complex, and their relationship with respiratory symptoms have been less thoroughly investigated. OBJECTIVE: In a pediatric population with partial ciliary defects, we determined the relationship(s) between ultrastructural findings, ciliary motility, and clinical and functional features, and evaluated the outcome of this population. DESIGN: We analyzed the clinical presentation and pulmonary function of 43 children with chronic bronchitis and partial ultrastructural defects (from 15% to 90%) of their respiratory cilia demonstrated on bronchial biopsies. The study population was divided into 3 groups according to ciliary ultrastructure: the main ultrastructural defect concerned the central complex in 23 patients (CC group), peripheral microtubules in 8 patients (PMT group), and DA in 12 patients (DA group). RESULTS: The percentage of ciliary defects was lower in the PMT group than in the CC and DA groups. Patients in the PMT group had less severe disease with frequent normal ciliary motility. Patients in the CC group had initially a higher incidence of respiratory tract infections, extensive bronchiectasis frequently requiring surgery, and arguments in favor of a congenital origin (high proportion of sibling form). Partial absence of DA, although of congenital origin, was associated with a good prognosis. In all groups, follow-up showed that the functional prognosis remained good with appropriate treatment. CONCLUSIONS: In children with chronic respiratory infections, presence of situs inversus, sibling form, obstructive pulmonary syndrome, or bronchiectasis required ultrastructural analysis, regardless of ciliary motility. Detection of CC abnormalities is a marker of severity and required intensive therapy and close follow-up.

Adolescent↗

PubMed2001

Six month administration of gelified intranasal insulin in 16 type 1 diabetic patients under multiple injections: efficacy vs subcutaneous injections and local tolerance.

OBJECTIVE: Nasal insulin administration is a potential route for intensive insulin management, less invasive and more rapid than subcutaneous injections. Previous studies have shown poor bioavailability (less than 15%) with nasal insulin administration with various absorption enhancers. The aim of the study was to evaluate in type 1 diabetic patients, the metabolic efficacy and local tolerance of a new gelified sprayed nasal insulin containing glychocolate and methylcellulose as absorption promoters. MATERIAL AND METHODS: The study was conducted in 16 type 1 diabetic patients (HbA1c 8.6+/-0.2%) in a cross-over trial including 2 six month randomized periods: a) NPH twice daily + 3 pre-prandial nasal insulin doses + nasal supplementation in case of unexpected hyperglycaemia; b) NPH twice daily + 3 pre-prandial regular insulin injections. End points were HbA1c levels, hypoglycaemic episodes and tolerance evaluated at month 0, 2, 6 and 8 on clinical symptoms and objective nasal assessments. RESULTS: Four patients were withdrawn because of nasal burning (3 cases) and persistent sinusitis (1 case), and one patient had purulent sinusitis at the month 6 examination. At month 6, HbA1c levels were comparable (8.3 +/- 0.1 vs 8.6 +/- 0.1%, m +/- SEM, NS) for nasal and subcutaneous period respectively. The number of hypoglycaemic events was identical during the 2 periods (88 episodes). Nasal tolerance with the gelified form was better than with the already reported lyophilized form but, when present, symptoms were more marked, suggesting a potentiating additional role of methylcellulose excipient on nasal intolerance. CONCLUSIONS: 1) Gelified nasal insulin is as efficient as subcutaneous regular insulin in type 1 diabetic patients. 2) Other galenic forms should be investigated to improve nasal tolerance and bioavailability.

Administration, Intranasal↗

PubMed2000

The human dynein intermediate chain 2 gene (DNAI2): cloning, mapping, expression pattern, and evaluation as a candidate for primary ciliary dyskinesia.

Primary ciliary dyskinesia (PCD) is an autosomal recessive disease characterized by chronic sinusitis and bronchiectasis, and usually associated with hypofertility. Half of the patients present a situs inversus, defining the Kartagener's syndrome. This phenotype results from axonemal abnormalities of respiratory cilia and sperm flagella, i.e., mainly an absence of dynein arms. Recently, a candidate-gene approach, based on documented abnormalities of immotile strains of Chlamydomonas reinhardtii, allowed us to identify the first gene involved in PCD. Following the same strategy, we have characterized DNAI2, a human gene related to Chlamzydomonas IC69, and evaluated its possible involvement in a PCD population characterized by an absence of outer dynein arms. DNAI2, which is composed of 14 exons located at 17q25, is highly expressed in trachea and testis. No mutation was found in the DNAI2 coding sequence of the twelve patients investigated. However, ten intragenic polymorphic sites and an EcoRI RFLP have been identified, allowing the exclusion of DNAI2 in three consanguineous families.

Adolescent↗

PubMed2000

Inflammatory cells as well as epithelial cells in nasal polyps express vascular endothelial growth factor.

In nasal polyps (NPs), locally secreted growth factors are involved in the remodelling of the epithelium and extracellular matrix but little is known concerning vessel remodelling. The in situ expression of vascular endothelial growth factor (VEGF) in NPs and control nasal mucosa (CM) were evaluated and in vitro secretion of VEGF from primary human cultures of nasal epithelial cells (HNECs) was quantified. VEGF expression was evaluated in NP (n=14) and CM (n=6) after immunolabelling. In supernatants from HNECs cultured at air/liquid interface, VEGF was quantified by immunoassay, under baseline conditions and after transforming growth factor-beta1 (TGF-beta1) stimulation. In HNEC lysates, VEGF and VEGF messenger ribonucleic acid (mRNA) were detected using Western blot analysis and reverse transcriptase polymerase chain reaction respectively. VEGF positivity was more frequent in inflammatory cells in NPs (14 of 14) than in CM (three of six) (p<0.05) and in the epithelium in NPs (six of 14) than in CM (two of six) (nonsignificant). Under baseline conditions, the VEGF concentration in HNEC culture medium increased from day 2 to 4, then decreased and became undetectable. VEGF concentrations increased significantly after TGF-beta1 stimulation. In HNEC lysates, VEGF and VEGF mRNA were detected on days 4 and 14 of culture. It was concluded that vascular endothelial growth factor is intensely expressed in situ in nasal polyps, mainly in inflammatory cells but also in epithelial cells. Human nasal epithelial cells are able to secrete in vitro vascular endothelial growth factor. Transforming growth factor-beta1 upregulates this secretion. This suggests that vascular endothelial growth factor, inducing oedema and angiogenesis, could be involved in the pathogenesis of nasal polyps.

Endothelial Growth Factors↗

PubMed2000

Relation of epidermal growth factor receptor expression to goblet cell hyperplasia in nasal polyps.

BACKGROUND: Because the epidermal growth factor receptor (EGFR) system regulates mucin production in airway epithelium, we hypothesized a role for this system in mucus hypersecretion that occurs in nasal polyposis. OBJECTIVE: We examined the relationship between goblet cell hyperplasia, EGFR expression, and inflammatory mediators produced by eosinophils and neutrophils in nasal polyp tissues. METHODS: Nasal polyp tissue samples from 8 patients and nasal turbinate biopsy specimens from 6 normal control subjects were examined for alcian blue/PAS staining, mucin MUC5AC (MUC5AC), and EGFR immunoreactivity and EGFR gene expression (in situ hybridization). We also examined the role of eosinophils and neutrophils in goblet cell hyperplasia. RESULTS: In control nasal mucosa alcian blue/periodic acid-Schiff- and MUC5AC-stained areas were 18.40% +/- 1.31% and 21.89% +/- 1.43%, respectively. In polyps the alcian blue/periodic acid-Schiff- and MUC5AC-stained areas were 51.30% +/- 5.85% and 52.07% +/- 6.58%, which was significantly larger than that found in control subjects (each comparison, P <.01). Four of 6 control specimens expressed EGFR messenger RNA and protein weakly in the epithelium. In polyps 4 of 8 specimens expressed EGFR gene and EGFR protein strongly; the EGFR-stained area was greater in hyperplastic than in pseudostratified epithelium. TNF-alpha immunoreactivity, expressed in eosinophils, was increased in EGFR-positive polyps compared with EGFR-negative polyps, suggesting a role for TNF-alpha in EGFR expression. Neutrophils were increased in the epithelium of EGFR-positive compared with EGFR-negative polyps, suggesting a role for these cells in mucin expression and in goblet cell degranulation. CONCLUSION: These data suggest a role for EGFR cascade in the regulation of goblet cell mucins in nasal polyps. Proof of concept will require clinical studies using selective EGFR inhibitors.

Cell Movement↗

PubMed2000

Characterization of inflammatory reaction in upper airways of cystic fibrosis patients.

Inflammatory cell populations have not been yet precisely evaluated in cystic fibrosis (CF) airways. We intended to characterize morphological modifications, inflammatory cell infiltration and cell proliferation in nasal tissues obtained from 15 CF patients and from 6 non-CF patients with nasal polyposis. Morphological analysis showed an intense inflammatory infiltration in CF and non-CF tissues with only few modifications in the epithelium from CF tissues. Inflammatory cell populations characterized by specific immunolabeling were quantified, showing a predominance of macrophages and T- and B-lymphocytes and only moderate numbers of neutrophils in CF tissues; in non-CF polyps, lymphocytes and eosinophils were abundant. Proliferating cell percentages quantified after proliferating cell nuclear antigen immunolabeling were 5.3+/-4.1% (mean +/- SD) in CF polyps and 3.1+/-1.2% in non-CF polyps in epithelium but were very low in lamina propria. Intense inflammation in nasal tissues from CF patients is therefore dominated by macrophages and lymphocytes rather than by neutrophils. While morphology is preserved, proliferation is high in epithelium from CF polyps. These findings should be regarded in the future for a better understanding of inflammation in CF airway disease.

Adolescent↗

PubMed2000

[Implication of extracellular matrix metalloproteinases in the course of chronic inflammatory airway diseases].

Matrix metalloproteinases (MMPs) are major proteolytic enzymes that are involved in extracellular matrix (ECM) turn over. MMP-2 (gelatinase A) and MMP-9 (gelatinase B) cleave type IV collagen, which is an important constituent of basement membrane. These enzymes play an important role in normal tissue homeostasis, but imbalance between MMPs and their tissue inhibitors (TIMPs) is thought to be a critical factor in regulating tissue remodeling. MMP-2 is produced by fibroblasts, endothelial, and epithelial cells, while MMP-9 is mainly produced by inflammatory cells. The role of MMPs was investigated through biochemical analysis or in situ expression, in the pathogenesis of two chronic inflammatory airway diseases, asthma and nasal polyposis. Both are characterized with the accumulation of active inflammatory cells, matrix remodeling and epithelial changes. Increased levels of MMP-9 and TIMP-1 were found in asthmatic subjects and NP. In NP, MMP-9 expression was detected in epithelial, endothelial and inflammatory cells. In this setting, MMP-9 could play a crucial role in the transmigration of basement membrane components by inflammatory cells leading to inflammatory cell accumulation and maintenance of inflammation in airway. Moreover, MMP-9 may contribute to cell migration, an important mechanism involved in the repair of the respiratory epithelium.

Asthma↗