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Ischemia of the lung causes extensive long-term pulmonary injury: an experimental study.

van der Kaaij NP, Kluin J, Haitsma JJ, den Bakker MA, Lambrecht BN, Lachmann B, de Bruin RW, Bogers AJ - Respir. Res. (2008)

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Cardio-Thoracic Surgery, Erasmus MC, Rotterdam, the Netherlands. npvdkaaij@gmail.com

ABSTRACT

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

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Related in: MedlinePlus

MMP-2 and MMP-9 zymography. Pro MMP-9 was not measurable in any of the samples and active MMP-9 was detectable in the BALf of sham-operated and LIRI animals on day 1. Pro and active MMP-2 is expressed constitutively in all animals. BALf = Broncho-Alveolar Lavage Fluid; LIRI = Lung Ischemia-Reperfusion Injury; MMP = Matrix MetalloProteinase.
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Figure 1: MMP-2 and MMP-9 zymography. Pro MMP-9 was not measurable in any of the samples and active MMP-9 was detectable in the BALf of sham-operated and LIRI animals on day 1. Pro and active MMP-2 is expressed constitutively in all animals. BALf = Broncho-Alveolar Lavage Fluid; LIRI = Lung Ischemia-Reperfusion Injury; MMP = Matrix MetalloProteinase.

Mentions: MMP-2 is expressed constitutively in all animals (Figure 1 and 2). However, the total amount of pro- and active MMP-2 and MMP-9 per microliter BALf is increased in LIRI animals on day 1 (Figure 2) (recovered volume did not differ between the groups). MMP activity per microgram protein in the BALf, does not differ between the groups (data not shown), which indicates that the increased activity after LIRI must be due to elevated alveolar serum proteins. After day 3, no differences were demonstrable between the groups.


Ischemia of the lung causes extensive long-term pulmonary injury: an experimental study.

van der Kaaij NP, Kluin J, Haitsma JJ, den Bakker MA, Lambrecht BN, Lachmann B, de Bruin RW, Bogers AJ - Respir. Res. (2008)

MMP-2 and MMP-9 zymography. Pro MMP-9 was not measurable in any of the samples and active MMP-9 was detectable in the BALf of sham-operated and LIRI animals on day 1. Pro and active MMP-2 is expressed constitutively in all animals. BALf = Broncho-Alveolar Lavage Fluid; LIRI = Lung Ischemia-Reperfusion Injury; MMP = Matrix MetalloProteinase.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2335107&req=5

Figure 1: MMP-2 and MMP-9 zymography. Pro MMP-9 was not measurable in any of the samples and active MMP-9 was detectable in the BALf of sham-operated and LIRI animals on day 1. Pro and active MMP-2 is expressed constitutively in all animals. BALf = Broncho-Alveolar Lavage Fluid; LIRI = Lung Ischemia-Reperfusion Injury; MMP = Matrix MetalloProteinase.
Mentions: MMP-2 is expressed constitutively in all animals (Figure 1 and 2). However, the total amount of pro- and active MMP-2 and MMP-9 per microliter BALf is increased in LIRI animals on day 1 (Figure 2) (recovered volume did not differ between the groups). MMP activity per microgram protein in the BALf, does not differ between the groups (data not shown), which indicates that the increased activity after LIRI must be due to elevated alveolar serum proteins. After day 3, no differences were demonstrable between the groups.

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Cardio-Thoracic Surgery, Erasmus MC, Rotterdam, the Netherlands. npvdkaaij@gmail.com

ABSTRACT

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Show MeSH
Related in: MedlinePlus