Asunto(s)
COVID-19/mortalidad , Neumonía Viral/mortalidad , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , COVID-19/diagnóstico , Causas de Muerte , Niño , Alemania , Humanos , Gripe Humana/diagnóstico , Gripe Humana/mortalidad , Persona de Mediana Edad , Prevalencia , Factores de Riesgo , Estaciones del Año , Adulto JovenAsunto(s)
Hemorragia/etiología , Hallazgos Incidentales , Intubación Intratraqueal/efectos adversos , Lipoma/complicaciones , Lipoma/diagnóstico , Tráquea/lesiones , Neoplasias de la Tráquea/complicaciones , Neoplasias de la Tráquea/diagnóstico , Anciano de 80 o más Años , Diagnóstico Diferencial , Humanos , Masculino , RiesgoRESUMEN
Phosphocholine-modified bacterial cell wall components are virulence factors enabling immune evasion and permanent colonization of the mammalian host, by mechanisms that are poorly understood. Recently, we demonstrated that free phosphocholine (PC) and PC-modified lipooligosaccharides (PC-LOS) from Haemophilus influenzae, an opportunistic pathogen of the upper and lower airways, function as unconventional nicotinic agonists and efficiently inhibit the ATP-induced release of monocytic IL-1ß. We hypothesize that H. influenzae PC-LOS exert similar effects on pulmonary epithelial cells and on the complex lung tissue. The human lung carcinoma-derived epithelial cell lines A549 and Calu-3 were primed with lipopolysaccharide from Escherichia coli followed by stimulation with ATP in the presence or absence of PC or PC-LOS or LOS devoid of PC. The involvement of nicotinic acetylcholine receptors was tested using specific antagonists. We demonstrate that PC and PC-LOS efficiently inhibit ATP-mediated IL-1ß release by A549 and Calu-3 cells via nicotinic acetylcholine receptors containing subunits α7, α9, and/or α10. Primed precision-cut lung slices behaved similarly. We conclude that H. influenzae hijacked an endogenous anti-inflammatory cholinergic control mechanism of the lung to evade innate immune responses of the host. These findings may pave the way towards a host-centered antibiotic treatment of chronic airway infections with H. influenzae.
Asunto(s)
Adenosina Trifosfato/farmacología , Células Epiteliales/metabolismo , Haemophilus influenzae/química , Interleucina-1beta/metabolismo , Lipopolisacáridos/química , Lipopolisacáridos/farmacología , Pulmón/citología , Fosforilcolina/química , Células A549 , Animales , Células Epiteliales/efectos de los fármacos , Humanos , Ratones , Nicotina/farmacología , Receptores Nicotínicos/metabolismoRESUMEN
BACKGROUND: This study was designed to evaluate the role of heat shock protein 90 (HSP90) in tumor progression of murine islet cell tumors. Blockade of HSP90 has recently been proposed as a therapeutic target, but effects in models of islet cell tumors with AUY922, a newly developed HSP90 inhibitor, have not been examined. MATERIAL AND METHODS: The carcinoid cell line BON-1 and the HSP90 inhibitor AUY922 were used to determine effects on signaling and growth in vitro. In vivo transgenic RIP1-Tag2 mice, which develop islet cell neoplasms, were treated with vehicle or AUY922 (25 mg/kg/twice per week) from week 5 until death. The resected pancreata were evaluated macroscopically and microscopically by immunohistochemistry. Quantitative real-time PCR was performed for HSP90 targets with RNA from islets isolated from treated and untreated RIP1-Tag2 mice. RESULTS: HSP90 blockade impaired constitutive and growth factor-induced signaling in vitro. Moreover, HSP90 inhibition attenuated in vitro cell growth in a dose-dependent manner. In vivo, AUY922 significantly reduced tumor volume by 92% compared to untreated controls (p = 0.000), and median survival in the used transgenic mouse model was prolonged (110 vs. 119 days; p = 0.75). Quantitative real-time PCR for downstream target genes of HSP90 demonstrated significant downregulation in the islet cell tumors of RIP1-Tag2 mice treated with AUY922, confirming our ability to achieve effective pharmacologic levels of AUY922 within the desired tissue site in vivo. CONCLUSION: This is the first study to show that the HSP90 antagonist AUY922 may provide a new option for therapy of islet cell neoplasms.