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


CONCLUSIONS
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.
van der Kaaij
Niels P
NP
Department of Cardio-Thoracic Surgery, Erasmus MC, Rotterdam, the Netherlands. npvdkaaij@gmail.com
Kluin
Jolanda
J
Haitsma
Jack J
JJ
den Bakker
Michael A
MA
Lambrecht
Bart N
BN
Lachmann
Burkhard
B
de Bruin
Ron W F
RW
Bogers
Ad J J C
AJ
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002199:Capillary Permeability; D002245:Carbon Dioxide / Q000097:blood; D004195:Disease Models, Animal; D000860:Hypoxia / Q000209:etiology / Q000473:pathology; D008168:Lung / Q000098:blood supply / Q000276:immunology / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D008170:Lung Compliance; D008171:Lung Diseases / Q000209:etiology* / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D016131:Lymphocyte Subsets / Q000276:immunology / Q000473:pathology; D016676:Macrophages, Alveolar / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009504:Neutrophils / Q000473:pathology; D010100:Oxygen / Q000097:blood; D011663:Pulmonary Surfactants / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000209:etiology* / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D013997:Time Factors; D052096:Warm Ischemia / Q000009:adverse effects*; D015431:Weight Loss
D015703:Antigens, CD; D011663:Pulmonary Surfactants; D002245:Carbon Dioxide; D020778:Matrix Metalloproteinase 2; C522363:Mmp2 protein, rat; D020780:Matrix Metalloproteinase 9; D010100:Oxygen