Sepsis Induces a Dysregulated Neutrophil Phenotype That Is Associated with Increased Mortality
Background. Neutrophil dysfunction in sepsis has been implicated in the pathogenesis of multiorgan failure; however, the role of neutrophil extracellular traps (NETs) remains uncertain. We aimed to determine the sequential changes in ex vivo NETosis and its relationship with mortality in patients wi...
Saved in:
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2018-01-01
|
| Series: | Mediators of Inflammation |
| Online Access: | http://dx.doi.org/10.1155/2018/4065362 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850106727953858560 |
|---|---|
| author | Jaimin M. Patel Elizabeth Sapey Dhruv Parekh Aaron Scott Davinder Dosanjh Fang Gao David R. Thickett |
| author_facet | Jaimin M. Patel Elizabeth Sapey Dhruv Parekh Aaron Scott Davinder Dosanjh Fang Gao David R. Thickett |
| author_sort | Jaimin M. Patel |
| collection | DOAJ |
| description | Background. Neutrophil dysfunction in sepsis has been implicated in the pathogenesis of multiorgan failure; however, the role of neutrophil extracellular traps (NETs) remains uncertain. We aimed to determine the sequential changes in ex vivo NETosis and its relationship with mortality in patients with sepsis and severe sepsis. Methods. This was a prospective observational cohort study enrolling 21 healthy age-matched controls and 39 sepsis and 60 severe sepsis patients from acute admissions to two UK hospitals. Patients had sequential bloods for the ex vivo assessment of NETosis in response to phorbol-myristate acetate (PMA) using a fluorometric technique and chemotaxis using time-lapse video microscopy. Continuous data was tested for normality, with appropriate parametric and nonparametric tests, whilst categorical data was analysed using a chi-squared test. Correlations were performed using Spearman’s rho. Results. Ex vivo NETosis was reduced in patients with severe sepsis, compared to patients with sepsis and controls (p=0.002). PMA NETosis from patients with septic shock was reduced further (p<0.001) compared to controls. The degree of metabolic acidosis correlated with reduced NETosis (p<0.001), and this was replicated when neutrophils from healthy donors were incubated in acidotic media. Reduced NETosis at baseline was associated with an increased 30-day (p=0.002) and 90-day mortality (p=0.014) in sepsis patients. These findings were accompanied by defects in neutrophil migration and delayed apoptosis. Resolution of sepsis was not associated with the return to baseline levels of NETosis or migration. Conclusions. Sepsis induces significant changes in neutrophil function with the degree of dysfunction corresponding to the severity of the septic insult which persists beyond physiological recovery from sepsis. The changes induced lead to the failure to effectively contain and eliminate the invading pathogens and contribute to sepsis-induced immunosuppression. For the first time, we demonstrate that reduced ex vivo NETosis is associated with poorer outcomes from sepsis. |
| format | Article |
| id | doaj-art-4e1fb329b4e346c38a0491bdbc2b6b45 |
| institution | OA Journals |
| issn | 0962-9351 1466-1861 |
| language | English |
| publishDate | 2018-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Mediators of Inflammation |
| spelling | doaj-art-4e1fb329b4e346c38a0491bdbc2b6b452025-08-20T02:38:46ZengWileyMediators of Inflammation0962-93511466-18612018-01-01201810.1155/2018/40653624065362Sepsis Induces a Dysregulated Neutrophil Phenotype That Is Associated with Increased MortalityJaimin M. Patel0Elizabeth Sapey1Dhruv Parekh2Aaron Scott3Davinder Dosanjh4Fang Gao5David R. Thickett6Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UKInstitute of Inflammation and Ageing, University of Birmingham, Birmingham, UKInstitute of Inflammation and Ageing, University of Birmingham, Birmingham, UKInstitute of Inflammation and Ageing, University of Birmingham, Birmingham, UKInstitute of Inflammation and Ageing, University of Birmingham, Birmingham, UKInstitute of Inflammation and Ageing, University of Birmingham, Birmingham, UKInstitute of Inflammation and Ageing, University of Birmingham, Birmingham, UKBackground. Neutrophil dysfunction in sepsis has been implicated in the pathogenesis of multiorgan failure; however, the role of neutrophil extracellular traps (NETs) remains uncertain. We aimed to determine the sequential changes in ex vivo NETosis and its relationship with mortality in patients with sepsis and severe sepsis. Methods. This was a prospective observational cohort study enrolling 21 healthy age-matched controls and 39 sepsis and 60 severe sepsis patients from acute admissions to two UK hospitals. Patients had sequential bloods for the ex vivo assessment of NETosis in response to phorbol-myristate acetate (PMA) using a fluorometric technique and chemotaxis using time-lapse video microscopy. Continuous data was tested for normality, with appropriate parametric and nonparametric tests, whilst categorical data was analysed using a chi-squared test. Correlations were performed using Spearman’s rho. Results. Ex vivo NETosis was reduced in patients with severe sepsis, compared to patients with sepsis and controls (p=0.002). PMA NETosis from patients with septic shock was reduced further (p<0.001) compared to controls. The degree of metabolic acidosis correlated with reduced NETosis (p<0.001), and this was replicated when neutrophils from healthy donors were incubated in acidotic media. Reduced NETosis at baseline was associated with an increased 30-day (p=0.002) and 90-day mortality (p=0.014) in sepsis patients. These findings were accompanied by defects in neutrophil migration and delayed apoptosis. Resolution of sepsis was not associated with the return to baseline levels of NETosis or migration. Conclusions. Sepsis induces significant changes in neutrophil function with the degree of dysfunction corresponding to the severity of the septic insult which persists beyond physiological recovery from sepsis. The changes induced lead to the failure to effectively contain and eliminate the invading pathogens and contribute to sepsis-induced immunosuppression. For the first time, we demonstrate that reduced ex vivo NETosis is associated with poorer outcomes from sepsis.http://dx.doi.org/10.1155/2018/4065362 |
| spellingShingle | Jaimin M. Patel Elizabeth Sapey Dhruv Parekh Aaron Scott Davinder Dosanjh Fang Gao David R. Thickett Sepsis Induces a Dysregulated Neutrophil Phenotype That Is Associated with Increased Mortality Mediators of Inflammation |
| title | Sepsis Induces a Dysregulated Neutrophil Phenotype That Is Associated with Increased Mortality |
| title_full | Sepsis Induces a Dysregulated Neutrophil Phenotype That Is Associated with Increased Mortality |
| title_fullStr | Sepsis Induces a Dysregulated Neutrophil Phenotype That Is Associated with Increased Mortality |
| title_full_unstemmed | Sepsis Induces a Dysregulated Neutrophil Phenotype That Is Associated with Increased Mortality |
| title_short | Sepsis Induces a Dysregulated Neutrophil Phenotype That Is Associated with Increased Mortality |
| title_sort | sepsis induces a dysregulated neutrophil phenotype that is associated with increased mortality |
| url | http://dx.doi.org/10.1155/2018/4065362 |
| work_keys_str_mv | AT jaiminmpatel sepsisinducesadysregulatedneutrophilphenotypethatisassociatedwithincreasedmortality AT elizabethsapey sepsisinducesadysregulatedneutrophilphenotypethatisassociatedwithincreasedmortality AT dhruvparekh sepsisinducesadysregulatedneutrophilphenotypethatisassociatedwithincreasedmortality AT aaronscott sepsisinducesadysregulatedneutrophilphenotypethatisassociatedwithincreasedmortality AT davinderdosanjh sepsisinducesadysregulatedneutrophilphenotypethatisassociatedwithincreasedmortality AT fanggao sepsisinducesadysregulatedneutrophilphenotypethatisassociatedwithincreasedmortality AT davidrthickett sepsisinducesadysregulatedneutrophilphenotypethatisassociatedwithincreasedmortality |