Proinflammatory Cytokines Induce Bronchial Hyperplasia and Squamous Metaplasia in Smokers: Implications for chronic obstructive pulmonary disease therapy.

in American Journal of Respiratory Cell and Molecular Biology (2012), 47(1), 67-79

Tracheobronchial squamous metaplasia is common in smokers and is associated with both airway obstruction in chronic obstructive pulmonary disease (COPD) and increased risk of lung cancer. Whereas this ... [more ▼]

Tracheobronchial squamous metaplasia is common in smokers and is associated with both airway obstruction in chronic obstructive pulmonary disease (COPD) and increased risk of lung cancer. Whereas this reversible epithelial replacement is almost always observed in association with chronic inflammation, the role of inflammatory mediators in the pathogenesis of squamous metaplasia is still unclear. In the present study, we investigated the implication of cigarette smoke-mediated pro-inflammatory cytokine up-regulation in the development and treatment of tracheobronchial epithelial hyperplasia and squamous metaplasia. By using immunohistological techniques, we showed a higher epithelial expression of TNFalpha, IL-1beta and IL-6 as well as an activation of NF-kappaB and AP-1/MAPK signalling pathways in the respiratory tract of smoking patients compared to the normal ciliated epithelium of non-smoking patients. In addition, we demonstrated that these signalling pathways strongly influence the proliferation and the differentiation state of in vitro generated normal human airway epithelial basal cells. Finally, we exposed mice to cigarette smoke for 16 weeks and demonstrated that anti-TNFalpha (etanercept), anti-IL-1beta (anakinra) and/or anti-IL-6R (tocilizumab) therapies significantly reduced epithelial hyperplasia and squamous metaplasia development. These data highlight the importance of soluble inflammatory mediators in the pathogenesis of tracheobronchial squamous metaplasia. Therefore, administration of pro-inflammatory cytokine antagonists may have clinical application in the management of COPD patients. [less ▲]

Hearing Preservation in Cochlear Implantation and Drug Treatment.

in Advances in Oto-Rhino-Laryngology (2010), 67

Insertion of an electrode array into the cochlea produces immediate damage to the inner ear, which is responsible for a hearing loss. In addition, a delayed hearing loss can be observed. In order to ... [more ▼]

Insertion of an electrode array into the cochlea produces immediate damage to the inner ear, which is responsible for a hearing loss. In addition, a delayed hearing loss can be observed. In order to maximize hearing preservation after insertion of an electrode and to enhance the performance of the cochlear implant, it has been proposed to deliver pharmacological agents to the inner ear. Molecules can be administered locally to the inner ear through a direct perilymphatic perfusion or through the round window membrane. These modalities of treatment have already been successfully applied to some patients with inner ear diseases. In this paper, we will review some basic aspects of drug delivery to the inner ear to prevent the degeneration of the neurosensory hair cells and auditory neurons, and the actual applicability to humans in order to maintain hearing function after the insertion of electrodes of a cochlear implant. [less ▲]

Ototoxic drugs: difference in sensitivity between mice and guinea pigs.

in Toxicology Letters (2010), 193(1), 41-9

The development of experimental animal models has played an invaluable role in understanding the mechanisms of neurosensory deafness and in devising effective treatments. The purpose of this study was to ... [more ▼]

The development of experimental animal models has played an invaluable role in understanding the mechanisms of neurosensory deafness and in devising effective treatments. The purpose of this study was to develop an adult mouse model of ototoxic drug-induced hearing loss and to compare the ototoxicity in the adult mouse to that in the well-described guinea pig model. Mice are a powerful model organism, especially due to the large availability of antibodies, probes and genetic mutants. In this study, mice (n=114) and guinea pigs (n=35) underwent systemic treatment with either kanamycin or cisplatin. Auditory brainstem responses showed a significant threshold shift in guinea pigs 2 weeks after the beginning of the ototoxic treatment, while there was no significant hearing impairment recorded in mice. Hair cells and neuronal loss were correlated with hearing function in both guinea pigs and mice. These results indicate that the mouse is not a good model for ototoxicity, which should be taken into consideration in all further investigations concerning ototoxicity-induced hearing loss. [less ▲]

Ototoxic drugs: Difference in sensitivity between mice and guinea pigs.

in Toxicology letters (2009)

The development of experimental animal models has played an invaluable role in understanding the mechanisms of neurosensory deafness and in devising effective treatments. The purpose of this study was to ... [more ▼]

The development of experimental animal models has played an invaluable role in understanding the mechanisms of neurosensory deafness and in devising effective treatments. The purpose of this study was to develop an adult mouse model of ototoxic drug-induced hearing loss and to compare the ototoxicity in the adult mouse to that in the well-described guinea pig model. Mice are a powerful model organism, especially due to the large availability of antibodies, probes and genetic mutants. In this study, mice (n=114) and guinea pigs (n=35) underwent systemic treatment with either kanamycin or cisplatin. Auditory brainstem responses showed a significant threshold shift in guinea pigs 2 weeks after the beginning of the ototoxic treatment, while there was no significant hearing impairment recorded in mice. Hair cells and neuronal loss were correlated with hearing function in both guinea pigs and mice. These results indicate that the mouse is not a good model for ototoxicity, which should be taken into consideration in all further investigations concerning ototoxicity-induced hearing loss. [less ▲]

Delayed GM-CSF treatment stimulates axonal regeneration and functional recovery in paraplegic rats via an increased BDNF expression by endogenous macrophages

in FASEB Journal (2006), 20(8), 12391241

Macrophages (monocytes/microglia) could play a critical role in central nervous system repair. We have previously found a synchronism between the regression of spontaneous axonal regeneration and the ... [more ▼]

Macrophages (monocytes/microglia) could play a critical role in central nervous system repair. We have previously found a synchronism between the regression of spontaneous axonal regeneration and the deactivation of macrophages 3-4 wk after a compression-injury of rat spinal cord. To explore whether reactivation of endogenous macrophages might be beneficial for spinal cord repair, we have studied the effects of granulocyte-macrophage colony stimulating factor (GM-CSF) in the same paraplegia model and in cell cultures. There was a significant, though transient, improvement of locomotor recovery after a single delayed intraperitoneal injection of 2 mu g GM-CSF, which also increased significantly the expression of Cr3 and brain-derived neurotrophic factor ( BDNF) by macrophages at the lesion site. At longer survival delays, axonal regeneration was significantly enhanced in GMCSF-treated rats. In vitro, BV2 microglial cells expressed higher levels of BDNF in the presence of GM-CSF and neurons cocultured with microglial cells activated by GM-CSF generated more neurites, an effect blocked by a BDNF antibody. These experiments suggest that GM-CSF could be an interesting treatment option for spinal cord injury and that its beneficial effects might be mediated by BDNF.-Bouhy, D., Malgrange, B., Multon, S., Poirrier, A. L., Scholtes, F., Schoenen, J., Franzen, R. Delayed GM-CSF treatment stimulates axonal regeneration and functional recovery in paraplegic rats via an increased BDNF expression by endogenous macrophages. [less ▲]

Spontaneous arachnoid cyst rupture in a previously asymptomatic child: a case report

in European Journal of Paediatric Neurology : Official Journal of the European Paediatric Neurology Society (2004), 8(5), 247-251

Arachnoid cysts are benign congenital cavities arising in the subarachnoid space. Non-traumatic subdural effusion of cerebrospinal fluid is a rare complication requiring surgical treatment. Case Report: A ... [more ▼]

Arachnoid cysts are benign congenital cavities arising in the subarachnoid space. Non-traumatic subdural effusion of cerebrospinal fluid is a rare complication requiring surgical treatment. Case Report: A 15-year-old boy was admitted to the hospital because of symptoms related to acute intracranial hypertension (headache and vomiting). The cerebral CT-scan revealed a subdural hygroma adjoining a voluminous Sylvian arachnoid cyst. Two arachnoid cysts were incidentally discovered 11 years before this dramatic complication. Moreover, the patient had suffered a cerebral concussion 2 years earlier, but interestingly did not develop cystic hemorrhage or rupture, contrary to numerous cases previously described in the literature. The location of the cysts and their regular follow-up did not allow foreseeing a cystic rupture. Hygroma evacuation was first performed after which a subdural peritoneal. shunting, using a programmable opening pressure valve, was implanted. Spontaneous rupture into the subdural space represents an unusual complication of arachnoid cysts. Clinical aspects, radiographic findings, pathogenesis and surgical management are described. It is important to point out that subdural hygroma or haematoma should never be excluded in the absence of trauma history, even in the case of small non-progressive cysts regularly supervised. (C) 2004 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved. [less ▲]