Surfactant Protein D Deficiency Aggravates Cigarette Smoke-Induced Lung Inflammation by Upregulation of Ceramide Synthesis

Cigarette smoke (CS) is the main cause of chronic obstructive pulmonary disease. Surfactant protein D (SP-D) is an important anti-inflammatory protein that regulates host immune defense in the lungs. Here, we investigated the role of SP-D in a murine model of CS-induced inflammation. Pulmonary SP-D localization and abundance was compared between smoker and non-smoker individuals. For in vivo studies, wildtype, and SP-D-deficient mice were exposed to CS for either 12 weeks or 3 days. Moreover, the effect of therapeutic administration of recombinant fragment of human SP-D on the acute CS-induced changes was evaluated. Pulmonary SP-D appeared with heterogenous expression in human smokers, while mouse lung SP-D was uniformly upregulated after CS exposure. We found that SP-D-deficient mice were more susceptible to CS-induced macrophage-rich airway inflammation. SP-D deficiency influenced local pro-inflammatory cytokine levels, with increased CCL3 and interleukin-6 but decreased CXCL1. Furthermore, CS exposure caused significant upregulation of pro-inflammatory ceramides and related ceramide synthase gene transcripts in SP-D-deficient mice compared to wildtype littermates. Administration of recombinant fragment of human SP-D (rfhSP-D) alleviated CS-induced macrophage infiltration and prevented induction of ceramide synthase gene expression. Finally, rfhSP-D treatment attenuated CS-induced human epithelial cell apoptosis in vitro. Our results indicate that SP-D deficiency aggravates CS-induced lung inflammation partly through regulation of ceramide synthesis and that local SP-D enrichment rescues CS-induced inflammation

Therapeutic Potential of Surfactant Protein D (SP-D): Regulation of Apoptosis, Efferocytosis and Lung Inflammation

Apoptosis is a process by which cells die in a silent and non-inflammatory way. This process is usually followed by efferocytosis, the uptake of apoptotic bodies by alveolar macrophages. Apoptosis and efferocytosis are important for maintaining baseline tissues homeostasis. Accumulation of dying cells is damaging in many ways for the tissues and is the cause of many inflammatory lung diseases. Surfactant protein D (SP-D) is a soluble innate immune protein present on the airway surface and other mucosal surfaces. SP-D has been shown to bind to dying cells and improve the phagocytosis of apoptotic cells and bodies. Dead cells have been shown to accumulate in the lung of SP-D knockout mice. However, the effect of SP-D on apoptotic pathways, apoptotic microparticle (MP) generation and MP-mediated inflammatory response are unknown. For my PhD project, I hypothesize that SP-D modulates the extrinsic pathway of apoptosis and enhances MP formation and uptake by alveolar macrophages while suppressing their inflammatory response. The studies conducted for this thesis uncovered that SP-D binds to T cells and delays the progression of Fas:Fas ligand (FasL) and TNF-α related apoptosis inducing ligand (TRAIL):TRAIL receptor-induced, but not TNF-α:TNF-α receptor-mediated apoptosis. SP-D does this by reducing caspase-8 and -3 activation, and the exposure of phosphatidylserine (PS) to the surface of apoptotic cells. The effect of SP-D is related to the extrinsic pathway with no effect on caspase-9 activation in the presence of caspase-8 inhibitor. Furthermore, when the caspase-9-mediated branch of intrinsic pathway is inhibited, SP-D shows the same caspase-8 reduction. Importantly, SP-D accelerates the release of apoptotic MPs and concomitantly increases their clearance by alveolar macrophages. Notably, SP-D indirectly enhances the clearance of MPs by increasing MP number, but not by increasing the uptake of MPs by alveolar macrophages. Also, SP-D suppresses MP-mediated IL-6 and TNF-α expression by alveolar macrophages after efferocytosis. Therefore, SP-D regulates baseline immune cell homeostasis and lung inflammation, and has a therapeutic potential in regulating apoptosis, MP generation, efferocytosis and airway inflammation.Ph.D.2018-12-19 00:00:0

The National and Global Impact of Systemic and Structural Violence on the Effective Prevention, Treatment, and Management of COVID-19 in African or Black Communities: Protocol for a Scoping Review

BackgroundAs COVID-19 ravages the globe and cases increase rapidly, countries are presented with challenging policy choices to contain and mitigate its spread. In Canada and globally, the COVID-19 pandemic has added a new stratum to the debate concerning the root causes of global and racial health inequities and disparities. Individuals who exist as targets of systemic inequities are not only more susceptible to contracting COVID-19, but also more likely to bear the greatest social, economic, and physical burdens. Therefore, data collection that focuses on the impact of COVID-19 on the lives and health of African/Black communities worldwide is needed to develop intersectional, culturally relative, antiracist/antioppression, and empowerment-centered interventions and social policies for supporting affected communities. ObjectiveThe primary objective of this review is to investigate the impact and management of COVID-19 among African/Black individuals and communities, and understand how anti-Black racism and intersectional violence impact the health of African/Black communities during the pandemic. Moreover, the study aims to explore research pertaining to the impact of COVID-19 on Black communities in the global context. We seek to determine how Black communities are impacted with regard to structural violence, systematic racism, and health outcomes, and the ways in which attempts have been made to mitigate or manage the consequences of the pandemic and other injurious agents. MethodsA systematic search of quantitative and qualitative studies published on COVID-19 will be conducted in MEDLINE (Ovid), Embase (Ovid), Cumulative Index to Nursing and Allied Health Literature (EBSCO), Cochrane Library, PsychInfo (Ovid), CAB Abstracts (Ovid), Scopus (Elsevier), Web of Science (Clarivate), and Global Index Medicus. To be included in the review, studies should present data on COVID-19 in relation to African/Black individuals, populations, and communities in the global sphere. Studies must discuss racism, oppression, antioppression, or systemic and structural violence and be published in English, French, Spanish, or Portuguese. According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews guidelines, the findings will be synthesized quantitatively and qualitatively through thematic analysis. The risk of bias will not be assessed. ResultsTitle, abstract, and full-text screening concluded in June 2022. Data collection is in progress and is expected to be completed by December 2022. Data analysis and drafting of the manuscript will be done thereafter. Findings from the scoping review are expected to be provided for peer review in 2023. ConclusionsThis review will collect important data and evidence related to COVID-19 in African/Black communities. The findings could help identify existing gaps in COVID-19 management in African/Black communities and inform future research paradigms. Furthermore, the findings could be applied to decision-making for health policy and promotion, and could potentially influence services provided by health care facilities and community organizations around the globe. International Registered Report Identifier (IRRID)DERR1-10.2196/4038

Developing Reporting Guidelines for Studies of HIV Drug Resistance Prevalence: Protocol for a Mixed Methods Study

BackgroundHIV drug resistance is a global health problem that limits the effectiveness of antiretroviral therapy. Adequate surveillance of HIV drug resistance is challenged by heterogenous and inadequate data reporting, which compromises the accuracy, interpretation, and usability of prevalence estimates. Previous research has found that the quality of reporting in studies of HIV drug resistance prevalence is low, and thus better guidance is needed to ensure complete and uniform reporting. ObjectiveThis paper contributes to the process of developing reporting guidelines for prevalence studies of HIV drug resistance by reporting the methodology used in creating a reporting item checklist and generating key insights on items that are important to report. MethodsWe will conduct a sequential explanatory mixed methods study among authors and users of studies of HIV drug resistance. The two-phase design will include a cross-sectional electronic survey (quantitative phase) followed by a focus group discussion (qualitative phase). Survey participants will rate the essentiality of various reporting items. This data will be analyzed using content validity ratios to determine the items that will be retained for focus group discussions. Participants in these discussions will revise the items and any additionally suggested items and settle on a complete reporting item checklist. We will also conduct a thematic analysis of the group discussions to identify emergent themes regarding the agreement process. ResultsAs of November 2021, data collection for both phases of the study is complete. In July 2021, 51 participants had provided informed consent and completed the electronic survey. In October 2021, focus group discussions were held. Nine participants in total participated in two virtual focus group discussions. As of May 2022, data are being analyzed. ConclusionsThis study supports the development of a reporting checklist for studies of HIV drug resistance by achieving agreement among experts on what items should be reported in these studies. The results of this work will be refined and elaborated on by a writing committee of HIV drug resistance experts and external reviewers to develop finalized reporting guidelines. International Registered Report Identifier (IRRID)DERR1-10.2196/3596

HIV Prevention and Treatment Interventions for Black Men Who Have Sex With Men in Canada: Scoping Systematic Review

BackgroundBlack men who have sex with men (MSM) experience disproportionately high HIV incidence globally. A comprehensive, intersectional approach (race, gender, and sexuality or sexual behavior) in understanding the experiences of Black MSM in Canada along the HIV prevention and care continuums has yet to be explored. ObjectiveThis scoping review aims to examine the available evidence on the access, quality, gaps, facilitators, and barriers of engagement and identify interventions relevant to the HIV prevention and care continuum for Black MSM in Canada. MethodsWe conducted a systematic database search, in accordance with the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) checklist, of the available studies on HIV health experience and epidemiology concerning Black MSM living with or without HIV in Canada and were published after 1983 in either English or French. Searched databases include MEDLINE, Excerpta, Cumulative Index to Nursing and Allied Health Literature, the Cochrane Library, the NHUS Economic Development Database, Global Health, PsycInfo, PubMed, Scopus, and Web of Science. From the 3095 articles identified, 19 met the inclusion criteria and were analyzed. ResultsBlack MSM in Canada consistently report multiple forms of stigma and lack of community support contributing to an increased HIV burden. They experience discrimination based on their intersectional identities while accessing HIV preventative and treatment interventions. Available data demonstrate that Black MSM have higher HIV incidences than Black men who have sex with women (MSW) and White MSM, and low preexposure prophylaxis knowledge and HIV literacy. Black MSM experience significant disparities in HIV prevention and care knowledge, access, and use. Structural barriers, including anti-Black racism, homophobia, and xenophobia, are responsible for gaps in HIV prevention and care continuums, poor quality of care and linkage to HIV services, as well as a higher incidence of HIV. ConclusionsConsidering the lack of targeted interventions, there is a clear need for interventions that reduce HIV diagnoses among Black MSM, increase access and reduce structural barriers that significantly affect the ability of Black MSM to engage with HIV prevention and care, and address provider’s capacity for care and the structural barriers. These findings can inform future interventions, programming, and tools that may alleviate this HIV inequity. International Registered Report Identifier (IRRID)RR2-10.1136/bmjopen-2020-04305

Checklist for studies of HIV drug resistance prevalence or incidence: rationale and recommended use

HIV drug resistance (HIVDR) is a major challenge to the effectiveness of antiretroviral therapy. Global efforts in addressing HIVDR require clear, transparent, and replicable reporting in HIVDR studies. We describe the rationale and recommended use of a checklist that should be included in reports of HIVDR incidence and prevalence. After preliminary consultations with experts on HIVDR and establishing the need for guidance on HIVDR reporting, we used a sequential, explanatory, mixed methods approach to create the checklist; together with the accompanying articles, the checklist was reviewed by the authors and validated externally. The checklist for studies on HIVDR prevalence or incidence (CEDRIC-HIV) includes 15 recommended items that would enhance transparency and facilitate interpretation, comparability, and replicability of HIVDR studies. CEDRIC-HIV will help authors of HIVDR studies prepare research reports and assist reviewers and editors in assessments of completeness of reporting. The checklist will also facilitate statistical pooling and interpretation of HIVDR data

Checklist for studies of HIV drug resistance prevalence or incidence: rationale and recommended use

HIV drug resistance (HIVDR) is a major challenge to the effectiveness of antiretroviral therapy. global efforts in addressing HIVDR require clear, transparent, and replicable reporting in HIVDR studies. we describe the rationale and recommended use of a checklist that should be included in reports of HIVDR incidence and prevalence. after preliminary consultations with experts on HIVDR and establishing the need for guidance on HIVDR reporting, we used a sequential, explanatory, mixed methods approach to create the checklist; together with the accompanying articles, the checklist was reviewed by the authors and validated externally. the checklist for studies on HIVDR prevalence or incidence (CEDRIC-HIV) includes 15 recommended items that would enhance transparency and facilitate interpretation, comparability, and replicability of HIVDR studies. CEDRIC-HIV will help authors of HIVDR studies prepare research reports and assist reviewers and editors in assessments of completeness of reporting. The checklist will also facilitate statistical pooling and interpretation of HIVDR data

Surfactant protein D deficiency aggravates cigarette smoke-induced lung inflammation by upregulation of ceramide synthesis

Cigarette smoke (CS) is the main cause of chronic obstructive pulmonary disease. Surfactant protein D (SP-D) is an important anti-inflammatory protein that regulates host immune defense in the lungs. Here, we investigated the role of SP-D in a murine model of CS-induced inflammation. Pulmonary SP-D localization and abundance was compared between smoker and non-smoker individuals. For in vivo studies, wildtype, and SP-D-deficient mice were exposed to CS for either 12 weeks or 3 days. Moreover, the effect of therapeutic administration of recombinant fragment of human SP-D on the acute CS-induced changes was evaluated. Pulmonary SP-D appeared with heterogenous expression in human smokers, while mouse lung SP-D was uniformly upregulated after CS exposure. We found that SP-D-deficient mice were more susceptible to CS-induced macrophage-rich airway inflammation. SP-D deficiency influenced local pro-inflammatory cytokine levels, with increased CCL3 and interleukin-6 but decreased CXCL1. Furthermore, CS exposure caused significant upregulation of pro-inflammatory ceramides and related ceramide synthase gene transcripts in SP-D-deficient mice compared to wildtype littermates. Administration of recombinant fragment of human SP-D (rfhSP-D) alleviated CS-induced macrophage infiltration and prevented induction of ceramide synthase gene expression. Finally, rfhSP-D treatment attenuated CS-induced human epithelial cell apoptosis in vitro. Our results indicate that SP-D deficiency aggravates CS-induced lung inflammation partly through regulation of ceramide synthesis and that local SP-D enrichment rescues CS-induced inflammation