Incidence of primary graft dysfunction after lung transplantation is altered by timing of allograft implantation

Cunningham, Peter; Maidstone, Robert; Durrington, Hannah J.; Venkateswaran, R.; Cypel, Marcelo; Keshavjee, Shaf; Gibbs, Julie; Loudon, A. S. I.; Chow, Chung‐Wai; Ray, David; Blaikley, John

doi:10.1136/thoraxjnl-2018-212021

Cited by 28 publications

(16 citation statements)

References 10 publications

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“…Included in this, mammalian immunity is strongly regulated by the circadian clockwork, driving the magnitude and nature of both innate and acquired responses (1). Macrophages, in particular, have a strong endogenous circadian clock, which drives inflammatory function (2)(3)(4). We have previously identified a role for the circadian clock in regulation of time-of-day variation in outcomes following pneumococcal infection (5), but the mechanisms responsible remain unknown.…”

mentioning

confidence: 99%

The clock gene Bmal1 inhibits macrophage motility, phagocytosis, and impairs defense against pneumonia

Kitchen

Cunningham

Poolman

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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106

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The circadian clock regulates many aspects of immunity. Bacterial infections are affected by time of day, but the mechanisms involved remain undefined. Here we show that loss of the core clock protein BMAL1 in macrophages confers protection against pneumococcal pneumonia. Infected mice show both reduced weight loss and lower bacterial burden in circulating blood. In vivo studies of macrophage phagocytosis reveal increased bacterial ingestion following Bmal1 deletion, which was also seen in vitro. BMAL1−/− macrophages exhibited marked differences in actin cytoskeletal organization, a phosphoproteome enriched for cytoskeletal changes, with reduced phosphocofilin and increased active RhoA. Further analysis of the BMAL1−/− macrophages identified altered cell morphology and increased motility. Mechanistically, BMAL1 regulated a network of cell movement genes, 148 of which were within 100 kb of high-confidence BMAL1 binding sites. Links to RhoA function were identified, with 29 genes impacting RhoA expression or activation. RhoA inhibition restored the phagocytic phenotype to that seen in control macrophages. In summary, we identify a surprising gain of antibacterial function due to loss of BMAL1 in macrophages, associated with a RhoA-dependent cytoskeletal change, an increase in cell motility, and gain of phagocytic function.

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mentioning

confidence: 99%

The clock gene Bmal1 inhibits macrophage motility, phagocytosis, and impairs defense against pneumonia

Kitchen

Cunningham

Poolman

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

106

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“…With this background, Workshop participants identified a critical need to elucidate how circadian clocks mediate various aspects of specific immunity. The potential clinical ramifications of such research are very broad, including, but not limited to, the treatment of autoimmunity (101), long-term preservation of organ function in transplanted organs such as the lung (102,103), cancer immunotherapy (104)(105)(106), establishment of allergic tolerance (107), "immune paralysis" that accompanies severe sepsis (100,108), and even age-related changes in immune function (109,110). A specific opportunity with high potential impact for public health is to achieve a better understanding of how the timing of immunization might influence the molecular and cellular processes underlying the establishment of protective immunity.…”

Section: Workhop-identified Opportunitiesmentioning

confidence: 99%

Perfect timing: circadian rhythms, sleep, and immunity — an NIH workshop summary

et al. 2020

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Recent discoveries demonstrate a critical role for circadian rhythms and sleep in immune system homeostasis. Both innate and adaptive immune responses-ranging from leukocyte mobilization, trafficking, and chemotaxis to cytokine release and T cell differentiation-are mediated in a time of day-dependent manner. The National Institutes of Health (NIH) recently sponsored an interdisciplinary workshop, "Sleep Insufficiency, Circadian Misalignment, and the Immune Response," to highlight new research linking sleep and circadian biology to immune function and to identify areas of high translational potential. This Review summarizes topics discussed and highlights immediate opportunities for delineating clinically relevant connections among biological rhythms, sleep, and immune regulation. Circadian rhythms are daily variations in behavior and biological activity that stem from an intrinsic ability of organisms to align themselves with the environmental 24-hour light/dark cycle. These rhythms originate from an internal biological clock that drives many aspects of human physiology, including the sleepwake cycle and daily variations in blood pressure, body temperature, and cortisol (1). A growing body of epidemiological evidence demonstrates an association between altering circadian timing through shift work or frequent time zone travel and increased rates of cardiovascular disorders, metabolic syndrome, and cancer (2-4). Clinical aspects of disease such as pain perception, asthma exacerbations, and myocardial infarctions are more common at certain times of day or night (5, 6). The discovery of the genetic basis for the circadian clock in the 1980s and 1990s has ushered in a new era in which long-appreciated circadian rhythms in physiology and clinical medicine are being reframed in terms of gene expression, metabolism, signal transduction, and cellular physiology (7). The translation of circadian discovery into strategies to improve the prevention and management of disease promises to be transformative, but at present, fundamental research is outpacing clinical application (Figure 1A). Much will depend on research identifying the critical mechanisms and targets to which circadian rhythm-based therapeutic strategies can be applied. An emerging example of exciting circadian discovery with potential clinical relevance is the intersection between circadian function and immune regulation (Figure 1B). The NIH recently sponsored a workshop entitled "Sleep Insufficiency, Circadian Misalignment, and the Immune Response" (May 16-17, 2019, Rockville, Maryland, USA). Its aim was to highlight basic and clinical advances linking sleep and circadian biology to immune dysfunction, thereby stimulating the application of circadian biology to translational medicine. The Workshop was cosponsored by four NIH institutes-the National Heart, Lung, and Blood Institute (NHLBI), National Institute on Aging (NIA), National Institute of Allergy and Infectious Diseases (NIAID), and National Institute on Alcohol Abuse and Alcoholism (NIAAA)-reflecting a...

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“…29 Naloxone infusion did not improve graft function. 30 Some previous opinions state that donor/recipient circadian mismatch resulted in allograft dysfunction 31 and was improved via melatonin administration. 32 Ex Vivo Lung Perfusion.…”

Section: Lung Transplantationmentioning

confidence: 99%

Noteworthy Literature Published in 2018 for Thoracic Organ Transplantation

Tawil

Adams

Nicoara

et al. 2019

Semin Cardiothorac Vasc Anesth

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Publications of note from 2018 are reviewed for the cardiothoracic transplant anesthesiologist. Strategies to expand the availability of donor organs were highlighted, including improved donor management, accumulating experience with increased-risk donors, ex vivo perfusion techniques, and donation after cardiac death. A number of reports examined posttransplant outcomes, including outcomes other than mortality, with new data-driven risk models. Use of extracorporeal support in cardiothoracic transplantation was a prominent theme. Major changes in adult heart allocation criteria were implemented, aiming to improve objectivity and transparency in the listing process. Frailty and prehabilitation emerged as targets of comprehensive perioperative risk mitigation programs.

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Incidence of primary graft dysfunction after lung transplantation is altered by timing of allograft implantation

Cited by 28 publications

References 10 publications

The clock gene Bmal1 inhibits macrophage motility, phagocytosis, and impairs defense against pneumonia

The clock gene Bmal1 inhibits macrophage motility, phagocytosis, and impairs defense against pneumonia

Perfect timing: circadian rhythms, sleep, and immunity — an NIH workshop summary

Noteworthy Literature Published in 2018 for Thoracic Organ Transplantation

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