RESUMO
The complement system, a key component of innate immunity, provides the first line of defense against bacterial infection; however, the COVID-19 pandemic has revealed that it may also engender severe complications in the context of viral respiratory disease. Here, we review the mechanisms of complement activation and regulation and explore their roles in both protecting against infection and exacerbating disease. We discuss emerging evidence related to complement-targeted therapeutics in COVID-19 and compare the role of the complement in other respiratory viral diseases like influenza and respiratory syncytial virus. We review recent mechanistic studies and animal models that can be used for further investigation. Novel knockout studies are proposed to better understand the nuances of the activation of the complement system in respiratory viral diseases.
Assuntos
COVID-19 , Influenza Humana , Vírus Sincicial Respiratório Humano , Animais , Humanos , Pandemias , Proteínas do Sistema ComplementoRESUMO
Emerging evidence indicates that activation of complement system leading to the formation of the membrane attack complex (MAC) plays a detrimental role in COVID-19. However, their pathogenic roles have never been experimentally investigated before. We used three knock out mice strains (1. C3-/-; 2. C7-/-; and 3. Cd59ab-/-) to evaluate the role of complement in severe COVID-19 pathogenesis. C3 deficient mice lack a key common component of all three complement activation pathways and are unable to generate C3 and C5 convertases. C7 deficient mice lack a complement protein needed for MAC formation. Cd59ab deficient mice lack an important inhibitor of MAC formation. We also used anti-C5 antibody to block and evaluate the therapeutic potential of inhibiting MAC formation. We demonstrate that inhibition of complement activation (in C3-/-) and MAC formation (in C3-/-. C7-/-, and anti-C5 antibody) attenuates severe COVID-19; whereas enhancement of MAC formation (Cd59ab-/-) accelerates severe COVID-19. The degree of MAC but not C3 deposits in the lungs of C3-/-, C7-/- mice, and Cd59ab-/- mice as compared to their control mice is associated with the attenuation or acceleration of SARS-CoV-2-induced disease. Further, the lack of terminal complement activation for the formation of MAC in C7 deficient mice protects endothelial dysfunction, which is associated with the attenuation of diseases and pathologic changes. Our results demonstrated the causative effect of MAC in severe COVID-19 and indicate a potential avenue for modulating the complement system and MAC formation in the treatment of severe COVID-19.
Assuntos
Antígenos CD59 , COVID-19 , Ativação do Complemento , Complexo de Ataque à Membrana do Sistema Complemento , Camundongos Knockout , SARS-CoV-2 , Animais , COVID-19/imunologia , COVID-19/patologia , COVID-19/virologia , Ativação do Complemento/imunologia , Complexo de Ataque à Membrana do Sistema Complemento/metabolismo , Complexo de Ataque à Membrana do Sistema Complemento/imunologia , Camundongos , SARS-CoV-2/imunologia , Antígenos CD59/metabolismo , Antígenos CD59/genética , Antígenos CD59/imunologia , Complemento C3/imunologia , Complemento C3/metabolismo , Complemento C3/genética , Camundongos Endogâmicos C57BL , Humanos , Complemento C5/imunologia , Complemento C5/metabolismo , Complemento C5/antagonistas & inibidores , Modelos Animais de DoençasRESUMO
BACKGROUND AND OBJECTIVE: Dexmedetomidine (Precedex®) has been linked to depressive hemodynamic effects and increased length of stay in the post-anesthesia care unit (PACU) when used in ambulatory phacoemulsification procedures. We aimed to determine the prevalence and impact of dexmedetomidine use during ambulatory vitreoretinal procedures. PATIENTS AND METHODS: This retrospective cohort study involved 9,666 adult vitrectomies. Cases were divided into groups by anesthesia type: general anesthesia (GA) and monitored anesthesia care (MAC). For each group, various factors were compared between those who did and did not receive dexmedetomidine. Chi-squared and t tests were used for comparisons. RESULTS: Changes in mean arterial pressure in the MAC group were -1.69 ± 0.23 mmHg for no dexmedetomidine patients and -6.31 ± 0.39 mmHg for dexmedetomidine patients (P < 0.01). In the GA group, mean arterial pressure was -6.1 ± 0.35 mmHg for no dexmedetomidine patients and -11.18 ± 0.88 mmHg for dexmedetomidine patients (P < 0.01). PACU Phase II time in the MAC group was 36.93 ± 0.37 minutes and 40.67 ± 0.86 minutes for no dexmedetomidine and dexmedetomidine patients, respectively (P < 0.01). In the GA group, PACU Phase II time was 58.63 ± 0.95 minutes and 65.19 ± 2.38 minutes for no dexmedetomidine and dexmedetomidine patients, respectively (P < 0.01). CONCLUSIONS: Dexmedetomidine use in vitrectomies was associated with significant PACU delays. These delays may stem from adverse hemodynamic effects. [Ophthalmic Surg Lasers Imaging Retina 2024;55:86-91.].