Experimental paperVentilator-induced lung injury (VILI) promotes ischemia/reperfusion lung injury (I/R) and NF-kB antibody attenuates both injuries☆,☆☆
Introduction
Despite refinements in lung preservation and improvements in surgical techniques and perioperative care, ischemia/reperfusion-induced lung injury (I/R) remains a significant cause of early morbidity and mortality after lung transplantation.1 However, other injuries such as ventilator-induced lung injury occurring in the donor before the procurement procedure and after transplantation might contribute to and amplify I/R.1, 2
The pathogenesis of I/R is still unclear. Hypoxia and mechanotransduction3 (no blood flow) during ischemia induces macrophages, endothelial cell or other cells to generate reactive oxygen species (ROS), activation of NADPH oxidase, nuclear factor-kappa B (NF-kB), and calcium/calmodulin-dependent nitric oxide synthase (NOS)4, 5, 6, 7 and proinflammatory cytokines,1 as well as up-regulation of molecules on cell surface membrane. During reperfusion (re-oxygenation), cytokines and ROS mediate neutrophil activation, rolling, and adherence to endothelial cells which further promote the release of their oxygen radicals, cytokines, and other mediators, beginning a complex cascade resulting in vascular injury and migration of neutrophil into interstitium and alveoli. This sequence is followed by more inflammatory cells being recruited into the interstitial spaces and alveoli.1
Mechanical ventilation is indispensable in support of patients with respiratory failure, anesthesia or lung transplant. However, application of positive pressure to the lung can cause damage known as ventilator-induced lung injury. The mechanical forces applied through ventilation may have deleterious effects in at least two ways: (1) through physical disruption of the tissues and cells and (2) through mechanotransduction which triggers aberrant activation of cellular mechanisms leading to severe inflammation.8, 9, 10 NF-kB7, 11, 12, 13, 14 plays a key role in these pathways. After activation, NF-kB binds to specific sequences in the promoter regions of target genes.15, 16 The rapid transcription of proinflammatory cytokines and chemokines begins and these mediators stimulate neutrophil recruitment. NF-kB induces the production of cellular adhesion molecules, which promote the binding and emigration of sequestered neutrophils. A cascade of inflammatory mediators induces severe lung injury. Therefore, targeting of NF-kB may be a promising therapy to reduce VILI or I/R.17
We postulated that anti-NF-kB antibody might attenuate both VILI and I/R. To our knowledge, there has been no study evaluating the use of anti-NF-kB antibody in inhibiting NF-kB activation in acute lung injury. Whether combined VILI and I/R has synergistic damage has not been well explored. In this study we attempt to explore both of these issues.
Section snippets
Preparation of isolated and perfused rat lung
This study was approved by the Institutional Review Board for the care of animal subjects, and the care and handling of the animals were in accordance with National Institutes of Health guidelines for ethical animal research. The isolated perfused lung in situ I/R model was described previously.18, 19
Briefly, male Sprague–Dawley rats weighing 250 ± 350 g were anesthetized intraperitoneally with sodium pentobarbital (20 ± 25 mg). A tracheotomy was performed and the lungs were ventilated using a
In VILI alone model
Compared to the VT5 group with small tidal volume (5 ml/kg), the VT15 group with larger tidal volume (15 ml/kg) had significantly higher LWG and Kfc; LWG of the VT10 group with moderate tidal volume (10 ml/kg) was higher than that in the VT5 group with small tidal volume (5 ml/kg). The LWG and Kfc in the VT15 + NF-kB group pretreated with NF-kB were significantly lower than those in the non-treatment VT15 group. These findings indicated tidal volume at 10 or 15 ml/kg caused VILI which can be
Discussion
To our knowledge, our report is the first to show anti-NF-kB antibody pretreatment to be beneficial in attenuating VILI or I/R or combined injury. Meanwhile, our study showed that mechanical ventilation with larger VT at 15 ml/kg or even with moderate VT at 10 ml/kg induced VILI. VILI or I/R produced similar permeability pulmonary edema which was reflected by increasing Kfc and LWG. Cytokine (IL-1β) up-regulation occurred in both injuries. Pathologic examination showed edema and inflammatory cell
Conflict of interest statement
None to declare.
Acknowledgments
This work was partly supported by the grants from the Taipei Veterans General Hospital (VGH92-320) and National Science Council of Taiwan (NSC92-2314-B-075-073).
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Part of the results were presented at the International Conference of American Thoracic Society, 20–24 May 2006, San Diego, USA.
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A Spanish translated version of the summary of this article appears as Appendix in the final online version at doi:10.1016/j.resuscitation.2008.02.028.