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ABSTRACT: This study investigated the optimal alveolar oxygen concentration and inflation pressure during ischemia that reduces lung ischemia-reperfusion injury (LIRI).
Male Sprague-Dawley rats (n = 66) underwent 150 minutes of left lung ischemia by hilar clamping at an airway inflation pressure (P) of 5 or 30 cm H(2)O and an oxygen (O) concentration of 0%, 30%, or 100% (P(5)O(0), P(5)O(30), P(5)O(100), P(30)O(0), P(30)O(30) and P(30)O(100) groups). Lungs preserved with 0% oxygen were inflated with 100% nitrogen. Measurements of arterial blood gas values, pulmonary compliance, histology, flow cytometry of bronchoalveolar lavage fluid were performed on day 2 postoperatively.
Inflation with 30 cm H(2)O resulted in increased partial pressure of arterial oxygen (Pao(2)) and lung compliance, decreased diffuse alveolar damage, and less infiltration of CD4(+) and CD8(+) lymphocytes and major histocompatibility complex class II-positive (MHCII(+)) antigen-presenting cells (APCs) in the left lung on day 2 compared with clamping at an airway inflation pressure of 5 cm H(2)O. The 100% oxygen groups demonstrated a lower Pao(2) and a decreased pulmonary compliance than 30% oxygen groups. More CD8(+) lymphocytes and MHCII(+) APCs were found in the P(5)O(100) group than in the P(5)O(0) and P(5)O(30) groups.
Alveolar inflation with a pressure of 30 cm H(2)O and an oxygen concentration of 30% decreases the severity of LIRI. The protective effect is mainly due to hyperinflation and, to a lesser extent, through oxygen concentration.
The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 03/2012; 31(5):531-7. · 3.54 Impact Factor
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The Annals of thoracic surgery 12/2009; 88(6):1743-4. · 3.74 Impact Factor
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ABSTRACT: This review addresses surfactant alterations and treatment in lung transplant ischemia–reperfusion injury. Lung ischemia–reperfusion injury damages the endogenous surfactant system as a result of the production of reactive oxygen species, proteolytic enzymes and (phospho)lipases. Surfactant is composed of phospholipids and proteins and its main function is to reduce the surface tension inside the alveolus. Impairment of surfactant will cause atelectasis, influx of serum proteins, pulmonary edema, decreased lung compliance and impaired gas exchange. Surfactant therapy restores the quantity and composition of surfactant and reduces the inhibitory effect of serum proteins; other effects are that it serves as an antioxidant and anti-inflammatory agent. Pretreatment may be more beneficial than treatment after the development of lung ischemia–reperfusion injury. However, the cost of surfactant must be weighed against the clinical outcome.
07/2009; 2(4):221-229.
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ABSTRACT: Lung ischemia-reperfusion injury (LIRI) is a risk factor for primary acute graft failure following lung transplantation. LIRI hereby contributes to morbidity and mortality after lung transplantation. We have previously shown that surfactant pretreatment ameliorates LIRI up to 1 week after reperfusion. However, the impact of surfactant pretreatment on long-term outcome following LIRI is unknown. Therefore, the objective of this study was to investigate the effect of surfactant pretreatment on long-term outcome following LIRI.
Male Sprague-Dawley rats (n=63) were randomized to receive intratracheally administered porcine surfactant (400mg/kg) or no pretreatment. One hour thereafter, animals underwent 120min of warm ischemia by clamping the bronchus, pulmonary artery and vein of the left lung. A third group was sham-operated; a fourth group served as unoperated controls. Animals were killed on day 30 or 90 after surgery. Arterial oxygenation and lung compliance were determined. Broncho-alveolar lavage fluid (BALf) was collected to assess surfactant function and alveolar protein. Leukocyte infiltration was determined by flowcytometry in BALf, lung tissue and thoracic lymph nodes. Lungs of three animals per group were used for histological assessment.
Lung compliance was lower on day 30 and day 90 after LIRI than in sham-operated controls (day 30 V(max) 6.1+/-2.1 vs 12.6+/-1.3, day 90 6.9+/-3.0 vs 12.1+/-1.6; C(max) day 30 0.49+/-0.17 vs 1.08+/-0.21, day 90 0.67+/-0.31 vs 1.11+/-0.17). Furthermore, the number of CD45RA(+)-lymphocytes in left lung tissue was decreased on day 90 compared to unoperated animals (230.633+/-96.770 vs 696.347+/-202.909) and the number of macrophages elevated in left BALf on day 90. HE slides of LIRI animals were scored as fibroproliferative with moderate atelectasis. Surfactant pretreatment improved lung compliance (V(max) day 30 11.7+/-1.8, day 90 11.1+/-1.2; C(max) day 30 1.04+/-0.23, day 90 1.16+/-0.21) and normalized the number of CD45RA(+)-lymphocytes (769.555+/-421.016) in left lung tissue. Furthermore lung architecture on HE slides was on return to normal. However, more CD5(+)CD4(+)-lymphocytes on day 30 (754.788+/-97.269 vs 430.409+/-109.909) and more macrophages on day 90 (2.144.000+/-630.633 vs 867.454+/-383.220) were measured in pretreated lung tissue compared to LIRI animals.
Severe LIRI caused extensive pulmonary injury up to 90 days postoperatively. Surfactant pretreatment normalized pulmonary function, but resulted in an increased number of CD5(+)CD4(+)-cells and macrophages in lung tissue.
European journal of cardio-thoracic surgery: official journal of the European Association for Cardio-thoracic Surgery 01/2009; 35(2):304-12; discussion 312. · 2.40 Impact Factor
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The Annals of thoracic surgery 01/2009; 86(6):1779-80. · 3.74 Impact Factor
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The Annals of thoracic surgery 06/2008; 85(5):1685. · 3.74 Impact Factor
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ABSTRACT: Lung ischemia-reperfusion injury (LIRI) is suggested to be a major risk factor for development of primary acute graft failure (PAGF) following lung transplantation, although other factors have been found to interplay with LIRI. The question whether LIRI exclusively results in PAGF seems difficult to answer, which is partly due to the lack of a long-term experimental LIRI model, in which PAGF changes can be studied. In addition, the long-term effects of LIRI are unclear and a detailed description of the immunological changes over time after LIRI is missing. Therefore our purpose was to establish a long-term experimental model of LIRI, and to study the impact of LIRI on the development of PAGF, using a broad spectrum of LIRI parameters including leukocyte kinetics.
Male Sprague-Dawley rats (n = 135) were subjected to 120 minutes of left lung warm ischemia or were sham-operated. A third group served as healthy controls. Animals were sacrificed 1, 3, 7, 30 or 90 days after surgery. Blood gas values, lung compliance, surfactant conversion, capillary permeability, and the presence of MMP-2 and MMP-9 in broncho-alveolar-lavage fluid (BALf) were determined. Infiltration of granulocytes, macrophages and lymphocyte subsets (CD45RA+, CD5+CD4+, CD5+CD8+) was measured by flowcytometry in BALf, lung parenchyma, thoracic lymph nodes and spleen. Histological analysis was performed on HE sections.
LIRI resulted in hypoxemia, impaired left lung compliance, increased capillary permeability, surfactant conversion, and an increase in MMP-2 and MMP-9. In the BALf, most granulocytes were found on day 1 and CD5+CD4+ and CD5+CD8+-cells were elevated on day 3. Increased numbers of macrophages were found on days 1, 3, 7 and 90. Histology on day 1 showed diffuse alveolar damage, resulting in fibroproliferative changes up to 90 days after LIRI.
The short-, and long-term changes after LIRI in this model are similar to the changes found in both PAGF and ARDS after clinical lung transplantation. LIRI seems an independent risk factor for the development of PAGF and resulted in progressive deterioration of lung function and architecture, leading to extensive immunopathological and functional abnormalities up to 3 months after reperfusion.
Respiratory research 02/2008; 9:28. · 3.36 Impact Factor
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ABSTRACT: To investigate whether surfactant pretreatment provides lung protection in an animal model of lung ischemia-reperfusion injury (LIRI).
Male Sprague-Dawley rats (n=100) were randomised to receive intratracheally administered surfactant or no pretreatment. One hour thereafter, animals underwent 120min of warm ischemia of the left lung, or were sham-operated. A third group served as healthy untreated controls. Animals were killed on day 1, 3 or 7. Blood gas values were measured and lung compliance was recorded. Broncho-alveolar lavage fluid (BALf) was obtained to assess the amount of alveolar protein, the ratio of small to large aggregate surfactant phospholipids (SA/LA ratio), and leukocyte infiltration (granulocytes, macrophages and lymphocytes, measured by Flow Cytometry).
LIRI resulted in a mortality rate of 17% and significantly decreased lung compliance and PaO(2) (day 1 and 3 P<0.001, day 7 P<0.05) as compared to sham-operated and healthy controls. On day 1 more protein was present in the alveoli of ischemic lungs (P<0.001) than in sham-operated and healthy controls. Furthermore, LIRI resulted in an increased SA/LA ratio in the left lung on day 1 (P<0.05) and caused infiltration of granulocytes (day 1, 3 and 7 (P<0.01)), macrophages (day 3 (P<0.05) and 7 (P<0.01) and lymphocytes (day 3 and 7 (P<0.01)) in the BALf as compared to sham-operated and healthy controls. Surfactant pretreatment improved survival, lung compliance (day 3 P<0.001) and PaO(2) (day 1, 3 (P<0.01 and 7 (P<0.05)). It also reduced protein leakage (P<0.05) and prevented an increase in the SA/LA ratio (P<0.01). Although the number of macrophages and granulocytes in the BALF was increased on day 1 and 3 (P<0.01) after surfactant pretreatment as compared to all other groups, the number of lymphocytes was reduced on day 3 (P<0.05).
The present study shows that surfactant pretreatment enhances recovery of lung function and lung mechanics after LIRI, resulting in normal parameters from day 3 onwards. Surfactant pretreatment in this LIRI model may provide useful information to improve donor lung function after lung transplantation.
European Journal of Cardio-Thoracic Surgery 05/2005; 27(5):774-82. · 2.55 Impact Factor
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ABSTRACT: Objective: To investigate whether surfactant pretreatment provides lung protection in an animal model of lung ischemia-reperfusion injury (LIRI). Methods: Male Sprague–Dawley rats (n=100) were randomised to receive intratracheally administered surfactant or no pretreatment. One hour thereafter, animals underwent 120 min of warm ischemia of the left lung, or were sham-operated. A third group served as healthy untreated controls. Animals were killed on day 1, 3 or 7. Blood gas values were measured and lung compliance was recorded. Broncho-alveolar lavage fluid (BALf) was obtained to assess the amount of alveolar protein, the ratio of small to large aggregate surfactant phospholipids (SA/LA ratio), and leukocyte infiltration (granulocytes, macrophages and lymphocytes, measured by Flow Cytometry). Results: LIRI resulted in a mortality rate of 17% and significantly decreased lung compliance and PaO2 (day 1 and 3 P<0.001, day 7 P<0.05) as compared to sham-operated and healthy controls. On day 1 more protein was present in the alveoli of ischemic lungs (P<0.001) than in sham-operated and healthy controls. Furthermore, LIRI resulted in an increased SA/LA ratio in the left lung on day 1 (P<0.05) and caused infiltration of granulocytes (day 1, 3 and 7 (P<0.01)), macrophages (day 3 (P<0.05) and 7 (P<0.01) and lymphocytes (day 3 and 7 (P<0.01)) in the BALf as compared to sham-operated and healthy controls. Surfactant pretreatment improved survival, lung compliance (day 3 P<0.001) and PaO2 (day 1, 3 (P<0.01 and 7 (P<0.05)). It also reduced protein leakage (P<0.05) and prevented an increase in the SA/LA ratio (P<0.01). Although the number of macrophages and granulocytes in the BALF was increased on day 1 and 3 (P<0.01) after surfactant pretreatment as compared to all other groups, the number of lymphocytes was reduced on day 3 (P<0.05). Conclusions: The present study shows that surfactant pretreatment enhances recovery of lung function and lung mechanics after LIRI, resulting in normal parameters from day 3 onwards. Surfactant pretreatment in this LIRI model may provide useful information to improve donor lung function after lung transplantation.
European Journal of Cardio-Thoracic Surgery.
