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Metabolic dysfunction in lymphocytes promotes postoperative morbidity

Metabolic dysfunction in lymphocytes promotes postoperative morbidity
Metabolic dysfunction in lymphocytes promotes postoperative morbidity
Perioperative lymphopenia has been linked with an increased risk of postoperative infectious complications, but the mechanisms remain unclear. We tested the hypothesis that bioenergetic dysfunction is an important mechanism underlying lymphopenia, impaired functionality and infectious complications. In two cohorts of patients (61-82 years old) undergoing orthopaedic joint replacement (n=417 and 328, respectively), we confirmed prospectively that preoperative lymphopenia (≤1.3 x 10(9)·l(-1); <20% white cell count; prevalence 15-18%) was associated with infectious complications (relative risk 1.5 (95% confidence interval 1.1-2.0); P=0.008) and prolonged hospital stay. Lymphocyte respirometry, mitochondrial bioenergetics and function were assessed (n=93 patients). Postoperative lymphocytes showed a median 43% fall (range: 26-65%; P=0.029; n=13 patients) in spare respiratory capacity, the extra capacity available to produce energy in response to stress. This was accompanied by reduced glycolytic capacity. A similar hypometabolic phenotype was observed in lymphocytes sampled preoperatively from chronically lymphopenic patients (n=21). This hypometabolic phenotype was associated with functional lymphocyte impairment including reduced T-cell proliferation, lower intracellular cytokine production and excess apoptosis induced by a range of common stressors. Glucocorticoids, which are ubiquitously elevated for a prolonged period postoperatively, generated increased levels of mitochondrial reactive oxygen species, activated caspase-1 and mature interleukin (IL)-1β in human lymphocytes, suggesting inflammasome activation. mRNA transcription of the NLRP1 inflammasome was increased in lymphocytes postoperatively. Genetic ablation of the murine NLRP3 inflammasome failed to prevent glucocorticoid-induced lymphocyte apoptosis and caspase-1 activity, but increased NLRP1 protein expression. Our findings suggest that the hypometabolic phenotype observed in chronically lymphopenic patients and/or acquired postoperatively increases the risk of postoperative infection through glucocorticoid activation of caspase-1 via the NLRP1 inflammasome.
1470-8736
423-437
Edwards, Mark R.
818201d5-7636-4292-9af8-7dd8bcd1fcb5
Sultan, Pervez
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Gutierrez Del Arroyo, Ana
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Whittle, John
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Karmali, Shamir N.
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Moonesinghe, S. Ramani
117f1e9b-1a63-4be2-b41c-e95dda807271
Haddad, Fares S.
d686a398-002d-45a4-a112-b6514b014030
Mythen, Michael G.
940f5be7-e5bc-4a90-94aa-09fdc658caad
Singer, Mervyn
87229716-c753-44ab-a382-3f93c1c5441d
Ackland, Gareth Lewis
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Edwards, Mark R.
818201d5-7636-4292-9af8-7dd8bcd1fcb5
Sultan, Pervez
0f8c8b38-2ae5-4932-bd27-2fad1f2dc0be
Gutierrez Del Arroyo, Ana
f4a19868-9b13-43ce-bed3-9c87629cd67f
Whittle, John
8bf73399-269b-4f7c-9ebc-03aafe791832
Karmali, Shamir N.
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Moonesinghe, S. Ramani
117f1e9b-1a63-4be2-b41c-e95dda807271
Haddad, Fares S.
d686a398-002d-45a4-a112-b6514b014030
Mythen, Michael G.
940f5be7-e5bc-4a90-94aa-09fdc658caad
Singer, Mervyn
87229716-c753-44ab-a382-3f93c1c5441d
Ackland, Gareth Lewis
06db7a16-fe7f-4c82-acd0-1e85e8fb991f

Edwards, Mark R., Sultan, Pervez, Gutierrez Del Arroyo, Ana, Whittle, John, Karmali, Shamir N., Moonesinghe, S. Ramani, Haddad, Fares S., Mythen, Michael G., Singer, Mervyn and Ackland, Gareth Lewis (2015) Metabolic dysfunction in lymphocytes promotes postoperative morbidity. Clinical Science, 129 (5), 423-437. (doi:10.1042/CS20150024).

Record type: Article

Abstract

Perioperative lymphopenia has been linked with an increased risk of postoperative infectious complications, but the mechanisms remain unclear. We tested the hypothesis that bioenergetic dysfunction is an important mechanism underlying lymphopenia, impaired functionality and infectious complications. In two cohorts of patients (61-82 years old) undergoing orthopaedic joint replacement (n=417 and 328, respectively), we confirmed prospectively that preoperative lymphopenia (≤1.3 x 10(9)·l(-1); <20% white cell count; prevalence 15-18%) was associated with infectious complications (relative risk 1.5 (95% confidence interval 1.1-2.0); P=0.008) and prolonged hospital stay. Lymphocyte respirometry, mitochondrial bioenergetics and function were assessed (n=93 patients). Postoperative lymphocytes showed a median 43% fall (range: 26-65%; P=0.029; n=13 patients) in spare respiratory capacity, the extra capacity available to produce energy in response to stress. This was accompanied by reduced glycolytic capacity. A similar hypometabolic phenotype was observed in lymphocytes sampled preoperatively from chronically lymphopenic patients (n=21). This hypometabolic phenotype was associated with functional lymphocyte impairment including reduced T-cell proliferation, lower intracellular cytokine production and excess apoptosis induced by a range of common stressors. Glucocorticoids, which are ubiquitously elevated for a prolonged period postoperatively, generated increased levels of mitochondrial reactive oxygen species, activated caspase-1 and mature interleukin (IL)-1β in human lymphocytes, suggesting inflammasome activation. mRNA transcription of the NLRP1 inflammasome was increased in lymphocytes postoperatively. Genetic ablation of the murine NLRP3 inflammasome failed to prevent glucocorticoid-induced lymphocyte apoptosis and caspase-1 activity, but increased NLRP1 protein expression. Our findings suggest that the hypometabolic phenotype observed in chronically lymphopenic patients and/or acquired postoperatively increases the risk of postoperative infection through glucocorticoid activation of caspase-1 via the NLRP1 inflammasome.

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e-pub ahead of print date: 20 April 2015
Published date: 1 September 2015

Identifiers

Local EPrints ID: 437032
URI: http://eprints.soton.ac.uk/id/eprint/437032
ISSN: 1470-8736
PURE UUID: 1434b67b-906a-4129-a990-88f3845b3f13

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Date deposited: 15 Jan 2020 17:32
Last modified: 16 Mar 2024 05:59

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Contributors

Author: Mark R. Edwards
Author: Pervez Sultan
Author: Ana Gutierrez Del Arroyo
Author: John Whittle
Author: Shamir N. Karmali
Author: S. Ramani Moonesinghe
Author: Fares S. Haddad
Author: Michael G. Mythen
Author: Mervyn Singer
Author: Gareth Lewis Ackland

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