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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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The number of inflammatory cells in BALf and lung tissue of the left (day 0–90) and right lung (day 0–7). Shown are (A) helper T-lymphocytes (CD5+CD4+), (B) cytotoxic T-lymphocytes (CD5+CD8+), and (C) B-lymphocytes (CD45RA+) in BALf; (D) helper T-lymphocytes, (E) cytotoxic T-lymphocytes, and (F) B-lymphocytes in lung tissue. Day 0 represents the baseline value measured in unoperated animals. BALf = Broncho-Alveolar Lavage Fluid. U = P < 0.05 versus unoperated animals. Sx-y = P < 0.05 versus sham-operated animals from day x until day y. Lx-y = P < 0.05 versus LIRI animals from day x until day y
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Figure 5: The number of inflammatory cells in BALf and lung tissue of the left (day 0–90) and right lung (day 0–7). Shown are (A) helper T-lymphocytes (CD5+CD4+), (B) cytotoxic T-lymphocytes (CD5+CD8+), and (C) B-lymphocytes (CD45RA+) in BALf; (D) helper T-lymphocytes, (E) cytotoxic T-lymphocytes, and (F) B-lymphocytes in lung tissue. Day 0 represents the baseline value measured in unoperated animals. BALf = Broncho-Alveolar Lavage Fluid. U = P < 0.05 versus unoperated animals. Sx-y = P < 0.05 versus sham-operated animals from day x until day y. Lx-y = P < 0.05 versus LIRI animals from day x until day y

Mentions: Sham operation did not result in infiltration of lymphocytes in BALf (Figure 5A–C this manuscript; see additional file 1, Table 4B). After LIRI, an infiltration of mainly CD5+CD4+ and CD5+CD8+ and to a lesser extent CD45RA+-lymphocytes occurred in mainly the left, but also right BALf. Lymphocyte infiltration peaked on day 3, with levels decreasing thereafter (Figure 5A–C this manuscript; see additional file 1, Table 4B and 5B).


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)

The number of inflammatory cells in BALf and lung tissue of the left (day 0–90) and right lung (day 0–7). Shown are (A) helper T-lymphocytes (CD5+CD4+), (B) cytotoxic T-lymphocytes (CD5+CD8+), and (C) B-lymphocytes (CD45RA+) in BALf; (D) helper T-lymphocytes, (E) cytotoxic T-lymphocytes, and (F) B-lymphocytes in lung tissue. Day 0 represents the baseline value measured in unoperated animals. BALf = Broncho-Alveolar Lavage Fluid. U = P < 0.05 versus unoperated animals. Sx-y = P < 0.05 versus sham-operated animals from day x until day y. Lx-y = P < 0.05 versus LIRI animals from day x until day y
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: The number of inflammatory cells in BALf and lung tissue of the left (day 0–90) and right lung (day 0–7). Shown are (A) helper T-lymphocytes (CD5+CD4+), (B) cytotoxic T-lymphocytes (CD5+CD8+), and (C) B-lymphocytes (CD45RA+) in BALf; (D) helper T-lymphocytes, (E) cytotoxic T-lymphocytes, and (F) B-lymphocytes in lung tissue. Day 0 represents the baseline value measured in unoperated animals. BALf = Broncho-Alveolar Lavage Fluid. U = P < 0.05 versus unoperated animals. Sx-y = P < 0.05 versus sham-operated animals from day x until day y. Lx-y = P < 0.05 versus LIRI animals from day x until day y
Mentions: Sham operation did not result in infiltration of lymphocytes in BALf (Figure 5A–C this manuscript; see additional file 1, Table 4B). After LIRI, an infiltration of mainly CD5+CD4+ and CD5+CD8+ and to a lesser extent CD45RA+-lymphocytes occurred in mainly the left, but also right BALf. Lymphocyte infiltration peaked on day 3, with levels decreasing thereafter (Figure 5A–C this manuscript; see additional file 1, Table 4B and 5B).

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