Elsevier

Neurobiology of Disease

Volume 41, Issue 2, February 2011, Pages 538-551
Neurobiology of Disease

The pathobiology of blast injuries and blast-induced neurotrauma as identified using a new experimental model of injury in mice

https://doi.org/10.1016/j.nbd.2010.10.025Get rights and content

Abstract

Current experimental models of blast injuries used to study blast-induced neurotrauma (BINT) vary widely, which makes the comparison of the experimental results extremely challenging. Most of the blast injury models replicate the ideal Friedländer type of blast wave, without the capability to generate blast signatures with multiple shock fronts and refraction waves as seen in real-life conditions; this significantly reduces their clinical and military relevance. Here, we describe the pathophysiological consequences of graded blast injuries and BINT generated by a newly developed, highly controlled, and reproducible model using a modular, multi-chamber shock tube capable of tailoring pressure wave signatures and reproducing complex shock wave signatures seen in theater. While functional deficits due to blast exposure represent the principal health problem for today's warfighters, the majority of available blast models induces tissue destruction rather than mimic functional deficits. Thus, the main goal of our model is to reliably reproduce long-term neurological impairments caused by blast. Physiological parameters, functional (motor, cognitive, and behavioral) outcomes, and underlying molecular mechanisms involved in inflammation measured in the brain over the 30 day post-blast period showed this model is capable of reproducing major neurological changes of clinical BINT.

Graphical abstract

Research highlights

► The model mimics physiological and functional changes seen in soldiers after blast. ► The newly designed shock tube is able to reproduce military relevant scenarios. ► Inflammation in the brain may contribute to neurological deficits after blast.

Introduction

The main blast effects of explosive devices are: 1) primary (caused by the blast wave itself); 2) secondary (caused by the fragments of debris propelled by the explosion); 3) tertiary (acceleration of whole or part of the body by the blast wind); and 4) quaternary (flash burns as a consequence of the transient but intense heat of the explosion (Mellor, 1988, Owen-Smith, 1981). Accumulating experimental and clinical evidence shows that blast wave can cause brain injury without inflicting penetrating wounds of the head (i.e., secondary blast effects) or “coup-countercoup” (i.e., acceleration/deceleration via tertiary blast effects) (Cernak and Noble-Haeusslein, 2010, Warden et al., 2009). While much effort has been devoted to the mitigation of other types of blast injury, it is only recently that the importance of primary blast-induced neurotrauma (BINT) has been recognized (Cernak et al., 1999, Ling et al., 2009, Martin et al., 2008, Warden et al., 2009).

One of the key prerequisites to understanding primary BINT and its sequelae is accurate characterization of the blast environment. Improvised Explosive Devices (IEDs), observed in Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF), vary in type and deployment with the primary source for explosive material being ordnance, particularly artillery shells. The blast generated from these IEDs is strongly governed by factors such as fill chemistry, scale, casing, shape, initiation, and immediate surroundings. Because of the range of possible blast threat scenarios, it is critical to identify a representative set of threat conditions for investigation and laboratory simulation, thus develop a military-relevant model that replicates the vital mechanisms of injury seen in theater (Cernak and Noble-Haeusslein, 2010).

Primary BINT is caused by complex mechanisms of systemic, local, and cerebral responses to blast exposure (Cernak and Noble-Haeusslein). Thus, understanding this unique pathological entity requires a holistic approach, taking into account all vital injury mechanisms, not only those induced by a direct interaction between the shock wave and the head. The current experimental models used in an attempt to study primary BINT differ widely, and include TBI models that deliver direct impact to the head without involving the other parts of the body (such as the fluid-percussion, controlled cortical impact, and air-gun-type compressed air-delivered models) (Dennis et al., 2009, Dewitt and Prough, 2009), as well as those that expose the whole body to overpressure (such as the shock tube and blast tube models or the open field blast conditions) (Bauman et al., 2009, Cernak et al., 1996, Cernak et al., 2001, Long et al., 2009, Saljo et al., 2009) (Axelsson et al., 2000, Cernak et al., 1990). The major challenge in modeling primary BINT using experimental animals is reproducing the essential components of military-relevant blast conditions while replicating pathological components or phases of clinical BINT seen in patients. Therefore, the first objectives of this study were to develop a highly controlled mouse model of blast injuries, and to establish the parameters necessary to cause reproducible mild, moderate, or severe trauma. Having established these parameters, we further characterized the pathobiology of mild and moderate BINT, the most frequent injury groups encountered in clinical practice, based on physiological and functional parameters as well as molecular mechanisms of inflammation in the brain.

Section snippets

Materials and methods

All protocols involving the use of animals complied with the Guide and Care and Use of Laboratory Animals published by NIH (DHEW publication NIH 85-23-2985), and were approved by the Johns Hopkins University Animal Use Committee.

Mortality and blast injury severity

Fig. 3 shows the mortality rates in animals at 24 h after being exposed to graded intensity shock waves. A position-dependence of mortality has been established, where the mild intensity shock wave (measured rupture pressure: 183 ± 14 kPa, i.e., 26.5 ± 2.1 psig; measured total pressure: 103 kPa, i.e. 14.9 psig) caused 5% mortality in animals in supine position and no-lethality in animals in prone position. Moreover, after moderate or severe intensity shock exposure, the corresponding mortality rates

The importance of blast injury and blast-induced neurotrauma research

The creation of a reliable animal model for BINT research with direct applicability to the theater conditions that Warfighters experience is vital to Force Readiness for a number of reasons. America's Armed Forces in Iraq and Afghanistan sustain injuries from almost daily exposure to explosions or blasts with more than 73% of all U.S. military casualties caused by rocket-propelled grenades, improvised explosive devices (IEDs), and land mines (Ritenour et al., 2010, Department of Defense,

Conclusion

We have developed a new model for graded blast-induced neurotrauma, which induces physiological changes and functional deficits in a strictly controlled and defined experimental setting with a potential to generate a physical environment comparable to military scenarios. The alterations in vital functions, memory and cognitive performance, and behavioral impairments are comparable with the symptoms of mild and moderate TBI in Warfighters who are exposed to blast. Changes in genes involved in

Funding source

This work was supported by the JHU/APL internal research and development funds and the JHU/APL-JHU SOM Partnership Grant. The sponsor did not influence the study design; data collection, analysis and interpretation of data; or the writing of the report.

Disclosure statement

None of the authors had any actual or potential conflict of interest including any financial, personal, or other relationships with other people or organizations within 3 years of beginning the work submitted that could inappropriately influence (bias) their work.

This work has not been published previously; it is not under consideration elsewhere and its publication is approved by all authors. Moreover, the Johns Hopkins University Applied Physics Laboratory, i.e., the institution where the

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