Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 5 de 5
Filtrar
1.
Proc Natl Acad Sci U S A ; 119(6)2022 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-35110404

RESUMO

G protein-coupled receptors (GPCRs) regulate many pathophysiological processes and are major therapeutic targets. The impact of disease on the subcellular distribution and function of GPCRs is poorly understood. We investigated trafficking and signaling of protease-activated receptor 2 (PAR2) in colitis. To localize PAR2 and assess redistribution during disease, we generated knockin mice expressing PAR2 fused to monomeric ultrastable green fluorescent protein (muGFP). PAR2-muGFP signaled and trafficked normally. PAR2 messenger RNA was detected at similar levels in Par2-mugfp and wild-type mice. Immunostaining with a GFP antibody and RNAScope in situ hybridization using F2rl1 (PAR2) and Gfp probes revealed that PAR2-muGFP was expressed in epithelial cells of the small and large intestine and in subsets of enteric and dorsal root ganglia neurons. In healthy mice, PAR2-muGFP was prominently localized to the basolateral membrane of colonocytes. In mice with colitis, PAR2-muGFP was depleted from the plasma membrane of colonocytes and redistributed to early endosomes, consistent with generation of proinflammatory proteases that activate PAR2 PAR2 agonists stimulated endocytosis of PAR2 and recruitment of Gαq, Gαi, and ß-arrestin to early endosomes of T84 colon carcinoma cells. PAR2 agonists increased paracellular permeability of colonic epithelial cells, induced colonic inflammation and hyperalgesia in mice, and stimulated proinflammatory cytokine release from segments of human colon. Knockdown of dynamin-2 (Dnm2), the major colonocyte isoform, and Dnm inhibition attenuated PAR2 endocytosis, signaling complex assembly and colonic inflammation and hyperalgesia. Thus, PAR2 endocytosis sustains protease-evoked inflammation and nociception and PAR2 in endosomes is a potential therapeutic target for colitis.


Assuntos
Colo/metabolismo , Endocitose/fisiologia , Corantes Fluorescentes/metabolismo , Inflamação/metabolismo , Dor/metabolismo , Receptor PAR-2/metabolismo , Animais , Arrestinas/metabolismo , Membrana Celular/metabolismo , Endossomos/metabolismo , Feminino , Gânglios Espinais/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Nociceptividade/fisiologia , Transdução de Sinais/fisiologia
2.
J Pediatr Surg ; 57(8): 1642-1648, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35065805

RESUMO

BACKGROUND: Extracorporeal Membrane Oxygenation (ECMO) is offered to patients with congenital diaphragmatic hernia (CDH) who are in severe respiratory and cardiac failure. We aim to describe the types of complications among these patients and their impact on survival. METHODS: A single-center, retrospective review of CDH patients cannulated onto ECMO between January 2005 and November 2020 was conducted. ECMO complications, as categorized by the Extracorporeal Life Support Organization (ELSO), were correlated with survival status. Descriptive statistics were used to compare observed complications between survivors and non-survivors. RESULTS: In our cohort of CDH neonates, 21% (54/258) were supported with ECMO, of whom, 61% (33/54) survived. Survivors and non-survivors were similar in baseline characteristics except for birthweight z-score (p = 0.043). Seventy percent of CDH neonates experienced complications during their ECMO run, with the most common categories being metabolic (48.1%) and mechanical (38.9%), followed by hemorrhage (22.2%), neurological (18.5%), renal (11.1%), pulmonary (7.4%), and cardiovascular (7.4%). The median number of complications per patient was higher in the non-survivor group  (2 (IQR: 1-4) vs 1 (IQR: 0-2), p = 0.043). In addition, mechanical (57.1% vs 27.3%, p = 0.045) and renal (28.6% vs 0%, p = 0.002) complications were more common among non-survivors compared to survivors. CONCLUSION: Complications occur frequently among ECMO-treated newborns with CDH, some of which have serious long-term consequences. Survivors had higher birth weight z-scores, shorter ECMO runs, and fewer complications per patient. Mechanical and renal complications were independently associated with mortality, emphasizing the utility of more focused strategies to target fluid balance and renal protection and to prevent circuit and cannula complications.


Assuntos
Oxigenação por Membrana Extracorpórea , Hérnias Diafragmáticas Congênitas , Doenças do Recém-Nascido , Estudos de Coortes , Oxigenação por Membrana Extracorpórea/efeitos adversos , Hérnias Diafragmáticas Congênitas/complicações , Hérnias Diafragmáticas Congênitas/terapia , Humanos , Recém-Nascido , Estudos Retrospectivos
3.
Biomaterials ; 285: 121536, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35533442

RESUMO

Soft polymer nanoparticles designed to disassemble and release an antagonist of the neurokinin 1 receptor (NK1R) in endosomes provide efficacious yet transient relief from chronic pain. These micellar nanoparticles are unstable and rapidly release cargo, which may limit the duration of analgesia. We examined the efficacy of stable star polymer nanostars containing the NK1R antagonist aprepitant-amine for the treatment of chronic pain in mice. Nanostars continually released cargo for 24 h, trafficked through the endosomal system, and disrupted NK1R endosomal signaling. After intrathecal injection, nanostars accumulated in endosomes of spinal neurons. Nanostar-aprepitant reversed mechanical, thermal and cold allodynia and normalized nociceptive behavior more efficaciously than free aprepitant in preclinical models of neuropathic and inflammatory pain. Analgesia was maintained for >10 h. The sustained endosomal delivery of antagonists from slow-release nanostars provides effective and long-lasting reversal of chronic pain.


Assuntos
Dor Crônica , Antagonistas dos Receptores de Neurocinina-1 , Animais , Aprepitanto/farmacologia , Aprepitanto/uso terapêutico , Dor Crônica/tratamento farmacológico , Endossomos , Camundongos , Antagonistas dos Receptores de Neurocinina-1/farmacologia , Antagonistas dos Receptores de Neurocinina-1/uso terapêutico , Polímeros/farmacologia
4.
ASAIO J ; 67(3): 245-249, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33627596

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic has placed extraordinary strain on global healthcare systems. Use of extracorporeal membrane oxygenation (ECMO) for patients with severe respiratory or cardiac failure attributed to COVID-19 has been debated due to uncertain survival benefit and the resources required to safely deliver ECMO support. We retrospectively investigated adult patients supported with ECMO for COVID-19 at our institution during the first 80 days following New York City's declaration of a state of emergency. The primary objective was to evaluate survival outcomes in patients supported with ECMO for COVID-19 and describe the programmatic adaptations made in response to pandemic-related crisis conditions. Twenty-two patients with COVID-19 were placed on ECMO during the study period. Median age was 52 years and 18 (81.8%) were male. Twenty-one patients (95.4%) had severe ARDS and seven (31.8%) had cardiac failure. Fifteen patients (68.1%) were managed with venovenous ECMO while 7 (31.8%) required arterial support. Twelve patients (54.5%) were transported on ECMO from external institutions. Twelve patients were discharged alive from the hospital (54.5%). Extracorporeal membrane oxygenation was used successfully in patients with respiratory and cardiac failure due to COVID-19. The continued use of ECMO, including ECMO transport, during crisis conditions was possible even at the height of the COVID-19 pandemic.


Assuntos
COVID-19/terapia , Oxigenação por Membrana Extracorpórea/métodos , Adolescente , Adulto , Idoso , COVID-19/mortalidade , Oxigenação por Membrana Extracorpórea/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , SARS-CoV-2 , Padrão de Cuidado , Resultado do Tratamento , Adulto Jovem
5.
J Pediatr Surg ; 55(12): 2548-2554, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32951890

RESUMO

The rapid spread of coronavirus disease 2019 (COVID-19) has exceeded the standard capacity of many hospital systems and led to an unprecedented scarcity of resources, including the already limited resource of extracorporeal membrane oxygenation (ECMO). With the large amount of critically ill patients and the highly contagious nature of the virus, significant consideration of ECMO candidacy is crucial for both appropriate allocation of resources as well as ensuring protection of health care personnel. As a leading pediatric ECMO program in the epicenter of the pandemic, we established new protocols and guidelines in order to continue caring for our pediatric patients while accepting adult patients to lessen the burden of our hospital system which was above capacity. This article describes our changes in consultation, cannulation, and daily care of COVID-19 positive patients requiring ECMO as well as discusses strategies for ensuring safety of our ECMO healthcare personnel and optimal allocation of resources. LEVEL OF EVIDENCE: Level V.


Assuntos
COVID-19/terapia , Oxigenação por Membrana Extracorpórea , Alocação de Recursos para a Atenção à Saúde , Adulto , Criança , Oxigenação por Membrana Extracorpórea/economia , Oxigenação por Membrana Extracorpórea/normas , Alocação de Recursos para a Atenção à Saúde/economia , Alocação de Recursos para a Atenção à Saúde/organização & administração , Humanos , Guias de Prática Clínica como Assunto , SARS-CoV-2
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA