Elsevier

Resuscitation

Volume 79, Issue 1, October 2008, Pages 147-154
Resuscitation

Experimental paper
Ventilator-induced lung injury (VILI) promotes ischemia/reperfusion lung injury (I/R) and NF-kB antibody attenuates both injuries,☆☆

https://doi.org/10.1016/j.resuscitation.2008.02.028Get rights and content

Summary

Rationale

Whether the ventilator-induced lung injury (VILI) superimposed on ischemia/reperfusion injury (I/R) causes synergistic damage has not been well explored. Whether nuclear factor-kappa B (NF-kB) antibody has protective effects for both injuries is also unknown.

Methods

I/R and VILI were produced in an isolated rat lung model. Hemodynamics, lung weight gain (LWG), capillary filtration coefficient (Kfc), cytokines, and lung pathology were assessed.

Results

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 infiltration in VILI or I/R. In addition, the alveoli were overdistended and even ruptured because of marked inhomogeneity of inflation in VILI. Furthermore, combined I/R and VILI produced further increases in Kfc, LWG, IL-1β, as well as more severe pathologic changes. Conversely, less permeability pulmonary edema, pathologic changes and IL-1 expression were found in groups pretreated with anti-NF-kB antibody.

Conclusion

VILI and I/R cause synergistic damage on the lung. I/R or VILI alone or combined can be attenuated by NF-kB antibody. NF-kB plays an important role in both forms of lung injury. We propose anti-NF-kB antibody pretreatment to be beneficial for VILI, I/R and lung transplantation.

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).

References (33)

  • G. Zhao et al.

    Anoxia-reoxygenation versus ischemia in isolated rat lungs

    Am J Physiol

    (1997)
  • A.B. Al Mehdi et al.

    Endothelial NADPH oxidase as the source of oxidants in lungs exposed to ischemia or high K+

    Circ Res

    (1998)
  • D. Dreyfuss et al.

    Ventilator-induced lung injury

    Am J Respir Crit Care Med

    (1998)
  • N.E. Vlahakis et al.

    State of art: cellular stress failure in ventilator-injured lungs

    Am J Respir Crit Care Med

    (2005)
  • S.D. Ross et al.

    Attenuation of lung reperfusion injury after transplantation using an inhibitor of nuclear factor-kB

    Am J Physiol Lung Cell Mol Physiol

    (2000)
  • J.J. Haddad

    Science review: redox and oxygen-sensitive transcription factors in the regulation of oxidant-mediated lung injury: role for nuclear factor-κB

    Crit Care

    (2002)
  • Cited by (37)

    • Protective effects of hydrogen inhalation during the warm ischemia phase against lung ischemia-reperfusion injury in rat donors after cardiac death

      2019, Microvascular Research
      Citation Excerpt :

      The resultant production of reactive oxygen species (ROS) plays a prominent role in the mechanism of lung IRI (Zhou et al., 2012). Chiang et al. (2008) demonstrated that overproduction of ROS during the ischemia-reperfusion process induced chromosomal recombination and promoted cytokine gene expression via NF-κB-mediated pathway. Furthermore, ROS induced histological changes and aggressively damaged cellular metabolism, including DNA, proteins, and lipids, ultimately leading to transplant-associated alterations in graft function or organ failure (de Perrot et al., 2003).

    • Penehyclidine hydrochloride preconditioning provides pulmonary and systemic protection in a rat model of lung ischaemia reperfusion injury

      2018, European Journal of Pharmacology
      Citation Excerpt :

      Reactive oxygen species play a key role in the development of LIRI (Sun et al., 2011; Ucar et al., 2005), and mediates inflammation in ARDS (Fink, 2002). Previous studies showed that Reactive oxygen species were related to the activation of inflammatory processes by inducing NF-κB activation (Chiang et al., 2008; Rahman et al., 2004). MDA is a marker of the damage caused by oxidative stress, while SOD levels are usually used to evaluate primary defences against cytotoxic reactive oxygen species (Fan et al., 2011).

    View all citing articles on Scopus

    Part of the results were presented at the International Conference of American Thoracic Society, 20–24 May 2006, San Diego, USA.

    ☆☆

    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.

    View full text