ABSTRACT
BACKGROUND AND PURPOSE: Despite the availability of a variety of treatment options, many asthma patients have poorly controlled disease with frequent exacerbations. Proteinase-activated receptor-2 (PAR2) has been identified in preclinical animal models as important to asthma initiation and progression following allergen exposure. Proteinase activation of PAR2 raises intracellular Ca2+ , inducing MAPK and ß-arrestin signalling in the airway, leading to inflammatory and protective effects. We have developed C391, a potent PAR2 antagonist effective in blocking peptidomimetic- and trypsin-induced PAR2 signalling in vitro as well as reducing inflammatory PAR2-associated pain in vivo. We hypothesized that PAR2 antagonism by C391 would attenuate allergen-induced acutely expressed asthma indicators in murine models. EXPERIMENTAL APPROACH: We evaluated the ability of C391 to alter Alternaria alternata-induced PAR2 signalling pathways in vitro using a human airway epithelial cell line that naturally expresses PAR2 (16HBE14o-) and a transfected embryonic cell line (HEK 293). We next evaluated the ability for C391 to reduce A. alternata-induced acutely expressed asthma indicators in vivo in two murine strains. KEY RESULTS: C391 blocked A. alternata-induced, PAR2-dependent Ca2+ and MAPK signalling in 16HBE14o- cells, as well as ß-arrestin recruitment in HEK 293 cells. C391 effectively attenuated A. alternata-induced inflammation, mucus production, mucus cell hyperplasia and airway hyperresponsiveness in acute allergen-challenged murine models. CONCLUSIONS AND IMPLICATIONS: To our best knowledge, this is the first demonstration of pharmacological intervention of PAR2 to reduce allergen-induced asthma indicators in vivo. These data support further development of PAR2 antagonists as potential first-in-class allergic asthma drugs.
Subject(s)
Asthma , Receptor, PAR-2 , Allergens , Alternaria/metabolism , Animals , Asthma/drug therapy , Asthma/metabolism , HEK293 Cells , Humans , MiceABSTRACT
In response to the coronavirus disease 2019 (COVID-19) pandemic, our NYU Langone Health Tisch/Kimmel/Orthopedic Hospital Consultation-Liaison (CL) Psychiatry service underwent a multifaceted transformation to become a primarily Virtual CL Psychiatry service. We aimed to provide the hospital system with comprehensive psychiatric consultation for all patients, regardless of isolation status, while preserving personal protective equipment and avoiding unnecessary exposure to COVID-19 for our team members. In this article, we discuss harnessing technology for video consultations and transforming the multiple facets of an academic CL Psychiatry Service to become a comprehensive, functioning virtual consultation team during the COVID-19 pandemic. We review the history, best practices, legal, and regulatory considerations of using telepsychiatry for psychiatric consultations, challenges to implementation across multiple clinical sites, and expansion of the liaison rote to include support of frontline colleagues. Finally, we provide the physician, trainee, and psychiatric nurse perspective as it relates to this transition.