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Function of granulocytes after burns and trauma, associations with pulmonary vascular permeability, acute respiratory distress syndrome, and immunomodulation
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background: Our innate immunesystem protects us from infections but, since its methods is not all specific for microorganisms, may also induce collateral damage.

Severe physical injury often proved deadly throughout evolution. Such injuries may induce massive collateral damage. Nowadays we can initiate advanced critical care for affected patients and save them from imminent trauma-related death. We are therefore faced with the fact that the collateral damage from the immune system may pose a major threat to the patient, the pathophysiology of which is not amenable to direct medical treatment and which leaves us with only passive supportive measures.

In this thesis we investigated the role of leucocytes under such circumstances.

Our main aim was to understand better the role of leucocytes in the development of increased vascular permeability after burns and trauma.

More specifically we investigated the impact of an injury on the function of leucocytes such as the dynamic change of certain cell-surface receptors on the leucocytes and in their numbers and immature forms. We wanted to find out if the increased pulmonary vascular permeability after a burn could be mediated through heparin binding protein (HBP) released from granuloctes, and whether HBP could be used as a biomarker for respiratory failure after trauma. We also wanted to confirm the possible role of histamine as a mediator of the systemic increase in vascular permeability after burns.

Methods: The dynamic change of cell-surface receptors was measured by flow-acquired cytometer scanning (FACS) on blood samples taken after burns. The concentrations of HBP after a burn and mechanical trauma were analysed in plasma. Pulmonary vascular permeability after a burn was assessed using transpulmonary thermodilution. The histamine turnover after a burn was assessed with high performance liquid chromatography (HPLC) for concentrations of histamine and methylhistamine in urine.

Results: We confirmed earlier investigations showing altered expression of receptors on leucocytes after a burn, receptors intimately associated with leucocyte functions (study I). In a pilot study of 10 patients we measured plasma concentrations of HBP and found them to be increased soon after a burn (study II). This finding was not confirmed in a larger, more extensive and specific study of 20 patients. We did, however, find an association between alterations in the number of leucocytes soon after a burn and pulmonary vascular permeability, indicating that they had a role in this process (study III).

In another study of trauma (non burn) we found an association between the concentration of HBP in early plasma-samples after injury and the development of ARDS, indicating that granulocytes and HBP have a role in its aetiology (study IV).

We found a small increase in urinary histamine and normal urinary methylhistamine concentrations but had anticipated a distinct increase followed by a decrease after reading the current papers on the subject. This indicates that the role of histamine as a mediator of increased vascular permeability after burns may have been exaggerated (study V).

Conclusions: We conclude that leucocytes are affected by burns and trauma, and it is likely that they contribute to the development of respiratory failure and acute respiratory distress syndrome (ARDS). HBP is a candidate biomarker for the early detection of ARDS after trauma, and the white blood count (WBC) is a useful biomarker for the detection of decreased oxygenation soon after a burn.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2013. , 72 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1362
Keyword [en]
ARDS, azurocidin, burn, CAP-37, critical care, granulocyte, HBP, histamine, intensive care, leucocyte, leukocyte, mediator, methylhistamine, MOF, oedema, neutrophil, permeability, PMN, trauma, vascular permeability
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-94513ISBN: 978-91-7519-632-9 (print)OAI: oai:DiVA.org:liu-94513DiVA: diva2:632579
Public defence
2013-09-05, Elsa Brändström salen, Campus US, Linköpings universitet, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2013-06-25 Created: 2013-06-25 Last updated: 2014-03-24Bibliographically approved
List of papers
1. Dynamics of leukocyte receptors after severe burns: An exploratory study
Open this publication in new window or tab >>Dynamics of leukocyte receptors after severe burns: An exploratory study
2011 (English)In: BURNS, ISSN 0305-4179, Vol. 37, no 2, 227-233 p.Article in journal (Refereed) Published
Abstract [en]

Background: Patients with burns are susceptible to organ failure, and there is indirect evidence that leukocytes may contribute to this process. They may change the expression of cell-surface receptors after certain stimuli, for example, the burn. We therefore aimed to assess the changes induced by the burn in the expression of leukocyte cell-surface receptors CD11b, CD14, CD16, and CD62L on the surface of PMNs and monocytes. We also wanted to examine the dynamics of this activation during the first week after the burn, and to relate it to the size of the injury. Methods: Ten patients with burns of andgt;15% (TBSA) were included in the study. Blood samples were collected on arrival and every consecutive morning during the first week. Healthy volunteers acted as controls. Results: PMN CD11b expression was increased. The extent of PMN CD11b expression correlated negatively to the size of the full thickness burn. Monocyte CD14 expression increased initially but there was no relation to the size of the burn. PMN CD16 expression decreased initially during the first days and the decrease was related to burn size. CD62L did not vary depending on the burn in either PMN or monocytes during the first week after the burn. Conclusion: This study showed that specific receptors on the surface of leukocytes (PMN CD11b, monocyte CD14 and PMN CD16) are affected by the burn. Expression of PMN CD11b and CD16 are related to burn size. Burn-induced effects on the expression of PMN receptors, such as PMN CD11b and CD16, may contribute to burn-induced infection susceptibility.

Place, publisher, year, edition, pages
Elsevier Science B.V., Amsterdam., 2011
Keyword
Burn, CD11, CD14, CD16, CD62, Granulocyte, Integrin, Monocyte, PMN, Trauma
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-67169 (URN)10.1016/j.burns.2010.08.015 (DOI)000288410900007 ()
Note
Original Publication: Joakim Johansson, Florence Sjögren, Mikael Bodelsson and Folke Sjöberg, Dynamics of leukocyte receptors after severe burns: An exploratory study, 2011, BURNS, (37), 2, 227-233. http://dx.doi.org/10.1016/j.burns.2010.08.015 Copyright: Elsevier Science B.V., Amsterdam. http://www.elsevier.com/Available from: 2011-04-01 Created: 2011-04-01 Last updated: 2013-06-25
2. Neutrophil-derived heparin binding protein-A mediator of increased vascular permeability after burns?
Open this publication in new window or tab >>Neutrophil-derived heparin binding protein-A mediator of increased vascular permeability after burns?
2009 (English)In: BURNS, ISSN 0305-4179, Vol. 35, no 8, 1185-1187 p.Article in journal (Refereed) Published
Abstract [en]

Increased vascular permeability and oedema formation constitute a major clinical challenge following burns. Several clinical studies show that leukocytes are systemically activated following burns. Neutrophils have the capability to increase vascular permeability via mechanisms thought to involve the release of heparin binding protein (HBP). We hypothesised that HBP is elevated in plasma after major burns due to a systemic inflammatory response and investigated plasma-HBP concentrations in 10 severely burned patients daily for 1 week following the burn. Five-fold higher levels in plasma-HBP concentration compared to a control group were detected on the first day after injury, followed by a steep reduction in the time-period that corresponds to the last part of the hyperpermeability phase. These data are in accordance with the hypothesis that HBP may function as a mediator of the early bum-induced increase in vascular permeability, and call for further studies to confirm a possible cause-and-effect relationship between HBP and oedema formation following burns.

Keyword
Azurocidin, Burn, CAP-37, HBP, Trauma, Vascular permeability
National Category
Engineering and Technology
Identifiers
urn:nbn:se:liu:diva-52834 (URN)10.1016/j.burns.2009.02.021 (DOI)
Available from: 2010-01-12 Created: 2010-01-12 Last updated: 2014-01-15Bibliographically approved
3. Dynamics of leucocytes correlate with increased pulmonary vascular permeability and decreased PaO2:FiO2 ratio early after major burns
Open this publication in new window or tab >>Dynamics of leucocytes correlate with increased pulmonary vascular permeability and decreased PaO2:FiO2 ratio early after major burns
Show others...
2009 (English)Manuscript (preprint) (Other academic)
Abstract [en]

Introduction: The lung is affected soon after a major burn as indicated by a decreased PaO2:FiO2 ratio. The exact mechanism underlying this is not known. Polymorphonuclear leucocytes (PMN) are activated systemically and their numbers are largely increased soon after a burn followed by a rapid decline to low normal or subnormal numbers within 24 hours, possibly by increased extravasation. Experimental data have supported the hypothesis that an important target for this extravasation is the lungs. Other studies also show that when PMN adhere to endothelial cells they increase vascular permeability, and this effect is mediated, at least in part, by release of heparin binding protein (HBP, also known as CAP-37 and azurocidin). We hypothesised that there is a relation between early increased pulmonary vascular permeability or a decreased PaO2:FiO2 ratio and the dynamic change in blood leucocytes after a burn, possibly mediated by the local release of HBP.

Material and methods: This is a prospective, descriptive, exploratory, singlecentre study at a national burn centre. We investigated the dynamic changes of leucocytes in blood, plasma concentrations of HBP, pulmonary vascular permeability index (PVPI) by thermodilution, and PaO2:FiO2 ratios in 20 patients during the first 21 days after a major burn (20% >total burn surface area %).

Results: Median total burn surface area was 40% (IQR 25-52) and full thickness burn 28% (IQR 2-39). There was a correlation between the early (<24 hours) alteration in circulating white blood cell count and both early increased vascular permeability in the lung (r=0.63, p=0.004) and the decreased oxygenation index defined as PaO2:FiO2 < 27 kPa (p=0.004). There were no associations between plasma concentrations of HBP and measured pulmonary vascular permeability or PaO2:FiO2 ratios.

Conclusions: The results indicate that trapping of leucocytes in the lung may be an important factor in early increased pulmonary vascular permeability and decrease of the PaO2:FiO2 ratio. Our data do not support the idea that HBP, assessed by systemic plasma concentrations, mediate this effect.

Keyword
ARDS, azurocidin, burn, CAP-37, HBP, leukocyte, mediator, permeability, PMN, trauma
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-94511 (URN)
Available from: 2013-06-25 Created: 2013-06-25 Last updated: 2013-06-25Bibliographically approved
4. Heparin-binding protein (HBP): an early marker of respiratory failure after trauma?
Open this publication in new window or tab >>Heparin-binding protein (HBP): an early marker of respiratory failure after trauma?
Show others...
2013 (English)In: Acta Anaesthesiologica Scandinavica, ISSN 0001-5172, E-ISSN 1399-6576, Vol. 57, no 5, 580-586 p.Article in journal (Refereed) Published
Abstract [en]

Background Trauma and its complications contribute to morbidity and mortality in the general population. Trauma victims are susceptible to acute respiratory distress syndrome (ARDS) and sepsis. Polymorphonuclear leucocytes (PMNs) are activated after trauma and there is substantial evidence of their involvement in the development of ARDS. Activated PMNs release heparin-binding protein (HBP), a granule protein previously shown to be involved in acute inflammatory reactions. We hypothesised that there is an increase in plasma HBP content after trauma and that the increased levels are related to the severity of the trauma or later development of severe sepsis and organ failure (ARDS). Methods and Material We investigated HBP in plasma samples within 36h from trauma in 47 patients admitted to a level one trauma centre with a mean injury severity score (ISS) of 26 (2134). ISS, admission sequential organ failure assessment (SOFA) and Acute Physiology and Chronic Health Evaluation (APACHE) II scores were recorded at admission. ARDS and presence of severe sepsis were determined daily during intensive care. Results We found no correlation between individual maximal plasma HBP levels at admission and ISS, admission SOFA or APACHE II. We found, however, a correlation between HBP levels and development of ARDS (P=0.026, n=47), but not to severe sepsis. Conclusion HBP is a potential biomarker candidate for early detection of ARDS development after trauma. Further research is required to confirm a casual relationship between plasma HBP and the development of ARDS.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2013
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-92696 (URN)10.1111/aas.12070 (DOI)000317432300006 ()
Note

Funding Agencies|Research and Development Unit, Jamtland County Council||Laerdal Foundation||Magn Bergvalls Foundation||LPS Medical Foundation||Cancer and Traffic Injury Fund||Carnegie Foundation||Karolinska Institutet||Swedish Society of Medicine||Stockholm County Council||

Available from: 2013-05-16 Created: 2013-05-16 Last updated: 2017-12-06
5. Urinary excretion of histamine and methylhistamine after burns
Open this publication in new window or tab >>Urinary excretion of histamine and methylhistamine after burns
2012 (English)In: Burns, ISSN 0305-4179, E-ISSN 1879-1409, Vol. 38, no 7, 1005-1009 p.Article in journal (Refereed) Published
Abstract [en]

Background: The increased vascular permeability seen after burn contribute to morbidity and mortality as it interferes with organ function and the healing process. Large efforts have been made to explore underlying pathophysiological mechanisms that generate increased vascular permeability after burns. Many different substances have been proposed as mediators of which histamine, serotonin and oxygen radicals are claimed most important. However, no specific blocker has convincingly been shown to be clinically effective. Early work has claimed increased histamine plasma-concentrations in humans after burn and data from animal models pointed at histamine as an important mediator. Modern human clinical studies investigating the role of histamine as a mediator of the generalized post burn increase in vascular permeability are lacking. less thanbrgreater than less thanbrgreater thanMethod: We examined histamine turnover by measuring the urinary excretion of histamine and methyl histamine for 48 h after burns in 8 patients (mean total burn surface area 24%). less thanbrgreater than less thanbrgreater thanResults: Over time, in this time frame and compared to healthy controls we found a small increase in the excretion of histamine, but no increase of its metabolite methylhistamine. less thanbrgreater than less thanbrgreater thanConclusion: Our findings do not support that histamine is an important mediator of the increased systemic vascular permeability seen after burn.

Place, publisher, year, edition, pages
Elsevier, 2012
Keyword
Burn, Histamine, Mediator, Oedema, Vascular permeability
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-85848 (URN)10.1016/j.burns.2012.02.014 (DOI)000310410300008 ()
Note

Funding Agencies|Research and Development Unit, Jamtland County Council, Sweden||

Available from: 2012-11-30 Created: 2012-11-30 Last updated: 2017-12-07

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