Integrative biology of injury in animals

Mechanical injury is a prevalent challenge in the lives of animals with myriad potential consequences for organisms, including reduced fitness and death. Research on animal injury has focused on many aspects, including the frequency and severity of wounding in wild populations, the short- and long-term consequences of injury at different biological scales, and the variation in the response to injury within or among individuals, species, ontogenies, and environmental contexts. However, relevant research is scattered across diverse biological subdisciplines, and the study of the effects of injury has lacked synthesis and coherence. Furthermore, the depth of knowledge across injury biology is highly uneven in terms of scope and taxonomic coverage: much injury research is biomedical in focus, using mammalian model systems and investigating cellular and molecular processes, while research at organismal and higher scales, research that is explicitly comparative, and research on invertebrate and non-mammalian vertebrate species is less common and often less well integrated into the core body of knowledge about injury. The current state of injury research presents an opportunity to unify conceptually work focusing on a range of relevant questions, to synthesize progress to date, and to identify fruitful avenues for future research. The central aim of this review is to synthesize research concerning the broad range of effects of mechanical injury in animals. We organize reviewed work by four broad and loosely defined levels of biological organization: molecular and cellular effects, physiological and organismal effects, behavioural effects, and ecological and evolutionary effects of injury. Throughout, we highlight the diversity of injury consequences within and among taxonomic groups while emphasizing the gaps in taxonomic coverage, causal understanding, and biological endpoints considered. We additionally discuss the importance of integrating knowledge within and across biological levels, including how initial, localized responses to injury can lead to long-term consequences at the scale of the individual animal and beyond. We also suggest important avenues for future injury biology research, including distinguishing better between related yet distinct injury phenomena, expanding the subjects of injury research to include a greater variety of species, and testing how intrinsic and extrinsic conditions affect the scope and sensitivity of injury responses. It is our hope that this review will not only strengthen understanding of animal injury but will contribute to building a foundation for a more cohesive field of ‘injury biology’.     

体外肝细胞损伤模型分子机制探讨

肝损伤是临床常见的危害人类健康的疾病,是各种原因引起肝脏疾病的共同的表现,也是各型肝病共同的病理基础。建立稳定可靠体外肝细胞损伤模型,对于肝损伤病理机制研究及有效防治肝损伤药物筛选提供了前提。针对肝细胞损伤分子机制不同,目前已成功建立基于免疫损伤、氧化损伤、脂肪损伤等体外肝细胞损伤模型,用于临床药物筛选及疗效作用机制研究,本文对目前常见体外肝细胞损伤模型及其发生的分子生物学机制进行探讨。     

Inhibition of in vivo DNA synthesis in regenerating rat liver following thermal injury

Hepatic repair and regeneration which is extremely important after thermal injuries can be inhibited by the acute inflammatory reaction. Since thermal injury initiates this acute inflammatory reaction, DNA synthesis was studied in the regenerating liver following this injury. In vivo incorporation of [3H]-thymidine into hepatic DNA, autoradiographic determination of a labeling index, and thymidine kinase activity were determined. Incorporation of [3H]-thymidine into hepatic DNA and labeling indices were markedly diminished at 24 hours if partial hepatectomy and thermal injury were carried out concurrently. After partial hepatectomy, the expected elevations in thymidine kinase activity were inhibited by the thermal injury (p less than 0.01) and elevation of serum fibrinogen, a marker of the acute phase reaction that normally follows thermal injury, was blunted by the partial hepatectomy (p less than 0.05). The combination of thermal injury and partial hepatectomy resulted in a greatly diminished DNA replicative response as compared to partial hepatectomy alone and suggests that multiplicative injury is more likely to result in multi-system failure.     

Cross sectional survey of socioeconomic variations in severity and mechanism of childhood injuries in Trent 1992-7

ObjectiveTo determine the relation between morbidity from injury and deprivation for different levels of injury severity and for different injury mechanisms for children aged 0-14 years.DesignCross sectional survey of routinely collected hospital admission data for injury 1992-7.Setting862 electoral wards in Trent Region.Subjects21 587 injury related hospital admissions for children aged 0-4 years and 35 042 admissions for children aged 5-14.ResultsBoth total number of admissions for injury and admissions for injuries of higher severity increased with increasing socioeconomic deprivation. These gradients were more marked for 0-4 year old children than 5-14 year olds. In terms of injury mechanisms, the steepest socioeconomic gradients (where the rate for the fifth of electoral wards with the highest deprivation scores was ⩾3 times that of the fifth with the lowest scores) were for pedestrian injuries (adjusted rate ratio 3.65 (95% confidence interval 2.94 to 4.54)), burns and scalds (adjusted rate ratio 3.49 (2.81 to 4.34)), and poisoning (adjusted rate ratio 2.98 (2.65 to 3.34)).ConclusionThere are steep socioeconomic gradients for injury morbidity including the most common mechanisms of injury. This has implications for targeting injury prevention interventions and resources.

What is already known on this topic?

There is a steep socioeconomic gradient for injury related mortalityThere is conflicting evidence regarding the socioeconomic gradient for injury morbidity, particularly with respect to different injury severity and injury mechanisms

What this study adds

A socioeconomic gradient for injury morbidity exists in children aged <15 years, particularly in those aged <5, which persist for different measures of injury severityThe socioeconomic gradient for injury mechanisms is steepest for pedestrian injuries, burns and scalds, and poisoning, which has implications for targeting injury prevention strategies     

Critical role of acrolein in secondary injury following ex vivo spinal cord trauma

The pathophysiology of spinal cord injury (SCI) is characterized by the initial, primary injury followed by secondary injury processes in which oxidative stress is a critical component. Secondary injury processes not only exacerbate pathology at the site of primary injury, but also result in spreading of injuries to the adjacent, otherwise healthy tissue. The lipid peroxidation byproduct acrolein has been implicated as one potential mediator of secondary injury. To further and rigorously elucidate the role of acrolein in secondary injury, a unique ex vivo model is utilized to isolate the detrimental effects of mechanical injury from toxins such as acrolein that are produced endogenously following SCI. We demonstrate that (i) acrolein-Lys adducts are capable of diffusing from compressed tissue to adjacent, otherwise uninjured tissue; (ii) secondary injury by itself produces significant membrane damage and increased superoxide production; and (iii) these injuries are significantly attenuated by the acrolein scavenger hydralazine. Furthermore, hydralazine treatment results in significantly less membrane damage 2 h following compression injury, but not immediately after. These findings support our hypothesis that, following SCI, acrolein is increased to pathologic concentrations, contributes significantly to secondary injury, and thus represents a novel target for scavenging to promote improved recovery.     

Role of heat shock protein 70 in hepatic ischemia-reperfusion injury in mice

It is well established that liver ischemia-reperfusion induces the expression of heat shock protein (HSP) 70. However, the biological function of HSP70 in this injury is unclear. In this study, we sought to determine the role of HSP70 in hepatic ischemia-reperfusion injury in mice. Male mice were subjected to 90 min of partial hepatic ischemia followed by up to 8 h of reperfusion. HSP70 was rapidly upregulated after reperfusion. To explore the function of HSP70, sodium arsenite (8 mg/kg iv) was injected before surgery. We found that this dose induced HSP70 expression within 6 h of treatment. Induction of HSP70 with arsenite resulted in a >50% reduction in liver injury as determined by serum transaminases and histology. In addition, arsenite similarly reduced liver neutrophil recruitment and liver nuclear factor-kappaB activation, and attenuated serum levels of tumor necrosis factor-alpha and macrophage inflammatory protein-2, but increased levels of interleukin (IL)-6. In HSP70 knockout mice, arsenite did not protect against liver injury but did reduce liver neutrophil accumulation. Arsenite-induced reductions in neutrophil accumulation in HSP70 knockout mice were found to be mediated by IL-6. To determine whether extracellular HSP70 contributed to the injury, recombinant HSP70 was injected before surgery. Intravenous injection of 10 microg of recombinant HSP70 had no effect on liver injury after ischemia-reperfusion. The data suggest that intracellular HSP70 is directly hepatoprotective during ischemia-reperfusion injury and that extracellular HSP70 is not a significant contributor to the injury response in this model. Targeted induction of HSP70 may represent a potential therapeutic option for postischemic liver injury.     

Pathophysiological analysis of combined burn and smoke inhalation injuries in sheep

We investigated the pathophysiological alterations seen with combined burn and smoke inhalation injuries by focusing on pulmonary vascular permeability and cardiopulmonary function compared with those seen with either burn or smoke inhalation injury alone. To estimate the effect of factors other than injury, the experiments were also performed with no injury in the same experimental setting. Lung edema was most severe in the combined injury group. Our study revealed that burn injury does not affect protein leakage from the pulmonary microvasculature, even when burn is associated with smoke inhalation injury. The severity of lung edema seen with the combined injury is mainly due to augmentation of pulmonary microvascular permeability to fluid, not to protein. Cardiac dysfunction after the combined injury consisted of at least two phases. An initial depression was mostly related to hypovolemia due to burn injury. It was improved by a large amount of fluid resuscitation. The later phase, which was indicated to be a myocardial contractile dysfunction independent of the Starling equation, seemed to be correlated with smoke inhalation injury.     

Frequency of injury and the ecology of regeneration in marine benthic invertebrates

Many marine invertebrates are able to regenerate lost tissue following injury, but regeneration can come at a cost to individuals in terms of reproduction, behavior and physiological condition, and can have effects that reach beyond the individual to impact populations, communities, and ecosystems. For example, removal and subsequent regeneration of clams' siphons, polychaetes' segments, and brittlestars' arms can represent significant energetic input to higher trophic levels. In marine soft-sediment habitats, injury changes infaunal bioturbation rates and thus secondarily influences sediment-mediated competition, adult-larval interactions, and recruitment success. The importance of injury and regeneration as factors affecting the ecology of marine invertebrate communities depends on the frequency of injury, as well as on individual capacity for, and speed of, regeneration. A key question to answer is: "How frequently are marine benthic invertebrates injured?" Here, I review the sources and the frequencies of injury in a variety of marine invertebrates from different benthic habitats, discuss challenges, and approaches for accurately determining injury rates in the field, consider evidence for species-specific, temporal and geographic variation in injury rates, and present examples of indirect effects of injury on marine invertebrates to illustrate how injury and regeneration can modify larger-scale ecological patterns and processes.     

SIRT6在缺血再灌注损伤中的作用机制及研究进展

缺血性损伤后恢复血液供应会导致缺血再灌注（ischemia reperfusion, IR）损伤,这会导致组织损伤进一步加剧。IR损伤伴随着一系列机制,包括谷氨酸兴奋性毒性、钙超载、氧化应激、炎症和细胞凋亡,最终导致细胞死亡。IR损伤过程均由Sirtuins家族调控,在Sirtuins家族中,特异性定位于细胞核中的SIRT6可以促进对DNA损伤和氧化应激的抵抗,抑制基因组的不稳定性,在代谢稳态中发挥作用,同时SIRT6在人重要脏器中处于高度表达状态。但SIRT6在IR损伤中研究较少,结合国内外最新的研究进展,对SIRT6在IR损伤中的作用进行了回顾性的总结和分析,希望对国内外学者对于SIRT6在IR损伤中的研究提供一些参考依据。     

miRNAs在脊髓损伤中作用的研究进展

脊髓损伤是一个重要的公共卫生难题,脊髓损伤可划分为三个病理生理阶段:原发性损伤期、继发性损伤期和慢性损伤期。基因表达的改变在脊髓损伤中起到了重要作用,miRNAs可以调控转录后所有基因的表达,所以miRNAs是脊髓损伤中一个很具有研究价值的研究对象。miRNAs是20-25碱基组成的非编码RNA,通过与靶mRNAs 3‘UTR结合下调其表达实现的对mRNA翻译进程的调控。miRNAs与中枢神经系统的发育、功能和疾病有密切关系。脊髓损伤后miRNAs通过调节中性粒细胞和炎性反应通路在炎性应答中起到了重要作用;miRNAs在细胞凋亡中表现出了复杂的功能,其表达的改变可能同时刺激和抑制凋亡;miRNAs可通过增强星形胶质细胞肥大和调节胶质瘢痕的进程;miRNAs的下调可能通过促进轴突靶向作用、神经元存活和轴突生长来促进损伤脊髓部位再生进程。目前脊髓损伤仍是现代医学的难题,对神经系统疾病中miRNAs作用的研究,为脊髓损伤治疗提供了一种新的治疗方案,也是将来研究中的热点。     

富血小板血浆在脊柱脊髓损伤治疗中的应用进展

富血小板血浆是近些年来比较热门的一种血液制品,其来源于自体,且制备方法简单,又富含大量血小板及多种生长因子,能够加速骨愈合,增强骨再生,促进软组织及神经损伤恢复,因此得到了广泛的关注。国内外的研究人员根据富血小板血浆所具有的特点,针对各个方面对其进行了大量的研究实验,并且在临床骨科疾病的治疗中也已经开始了实验性应用,如骨缺损、骨再生,肌腱、韧带及软组织损伤,脊柱脊髓损伤等。尤其是在脊柱脊髓损伤的治疗方面,无论是单独应用富血小板血浆治疗,还是联合应用富血小板血浆与脊髓神经前体细胞、骨髓间充质干细胞等有利于脊髓神经损伤恢复的细胞因子复合物共同治疗,均取得了突破性的进展,为研究脊柱脊髓损伤的治疗提供了新的方向。     

The role of neuromuscular inhibition in hamstring strain injury recurrence

Hamstring strain injuries are amongst the most common and problematic injuries in a wide range of sports that involve high speed running. The comparatively high rate of hamstring injury recurrence is arguably the most concerning aspect of these injuries. A number of modifiable and nonmodifiable risk factors are proposed to predispose athletes to hamstring strains. Potentially, the persistence of risk factors and the development of maladaptations following injury may explain injury recurrence. Here, the role of neuromuscular inhibition following injury is discussed as a potential mechanism for several maladaptations associated with hamstring re-injury. These maladaptations include eccentric hamstring weakness, selective hamstring atrophy and shifts in the knee flexor torque-joint angle relationship. Current evidence indicates that athletes return to competition after hamstring injury having developed maladaptations that predispose them to further injury. When rehabilitating athletes to return to competition following hamstring strain injury, the role of neuromuscular inhibition in re-injury should be considered.     

The role of autophagy in spinal cord injury

Previous studies have indicated that autophagy has an important function, not only in many neurodegenerative diseases, but also in traumatic and ischemic brain injury. However, no study has previously shown the contribution of autophagy to neural tissue damage after spinal cord injury. We recently investigated that the alterations in Beclin 1 expression and the involvement of autophagy and autophagic cell death after spinal cord injury using a spinal cord hemisection model in mice. The results showed that the expression of Beclin 1 dramatically increased in the damaged neural tissue and induced autophagic cell death after a spinal cord injury. These observations suggested that the increased expression of Beclin1 activates autophagy, while mediating a novel cell death mechanism at the lesion site in response to spinal cord injury. Here we discuss several unsolved issues and review the evidence in related articles regarding the role of autophagy and its contribution to the mechanism of cell death in spinal cord injury.     

The role of Toll-like receptors in non-infectious lung injury

The role of Toll-like receptors （TLRs） in pathogen recognition has been expeditiously advanced in recent years. However, investigations into the function of TLRs in non-infectious tissue injury have just begun. Previously, we and others have demonstrated that fragmented hyaluronan （HA） accumulates during tissue injury. CD44 is required to clear HA during tissue injury, and impaired clearance of HA results in unremitting inflammation. Additionally, fragmented HA stimulates the expression of inflammatory genes by inflammatory cells at the injury site. Recently, we identified that HA fragments require both TLR2 and TLR4 to stimulate mouse macrophages to produce inflammatory chemokines and cytokines. In a non-infectious lung injury model, mice deficient in both TLR2 and TLR4 show an impaired transepithelial migration of inflammatory cells, increased tissue injury, elevated lung epithelial cell apoptosis, and decreased survival. Lung epithelial cell overexpression of high molecular mass HA protected mice against acute lung injury and apoptosis, in part through TLR-dependent basal activation of NF-κB. The exaggerated injury in TLR2 and TLR4 deficient mice appears to be due to impaired HA-TLR interactions on epithelial cells. These studies identify that host matrix component HA and TLR interactions provide signals that initiate inflammatory responses, maintain epithelial cell integrity, and promote recovery from acute lung injury.     

Alterations in calcium-mediated signal transduction after traumatic injury of cortical neurons

Calcium influx and elevation of intracellular free calcium ([Ca2+]i), with subsequent activation of degradative enzymes, is hypothesized to cause cell injury and death after traumatic brain injury. We examined the effects of mild-to-severe stretch-induced traumatic injury on [Ca2+]i dynamics in cortical neurons cultured on silastic membranes. [Ca2+]i was rapidly elevated after injury, however, the increase was transient with neuronal [Ca2+]i returning to basal levels by 3 h after injury, except in the most severely injured cells. Despite a return of [Ca2+]i to basal levels, there were persistent alterations in calcium-mediated signal transduction through 24 h after injury. [Ca2+]i elevation in response to glutamate or NMDA was enhanced after injury. We also found novel alterations in intracellular calcium store-mediated signaling. Neuronal calcium stores failed to respond to a stimulus 15 min after injury and exhibited potentiated responses to stimuli at 3 and 24 h post-injury. Thus, changes in calcium-mediated cellular signaling may contribute to the pathology that is observed after traumatic brain injury.     

Regulation of metabolism by mitochondrial enzyme acetylation in cardiac ischemia-reperfusion injury

Ischemia reperfusion injury (I/R injury) contributes significantly to morbidity and mortality following myocardial infarction (MI). Although rapid reperfusion of the ischemic myocardium was established decades ago as a highly beneficial therapy for MI, significant cell death still occurs after the onset of reperfusion. Mitochondrial dysfunction is closely associated with I/R injury, resulting in the uncontrolled production of reactive oxygen species (ROS). Considerable efforts have gone into understanding the metabolic perturbations elicited by I/R injury. Recent work has identified the critical role of reversible protein acetylation in maintaining normal mitochondrial biologic function and energy metabolism both in the normal heart and during I/R injury. Several studies have shown that modification of class I HDAC and/or Sirtuin (Sirt) activity is cardioprotective in the setting of I/R injury. A better understanding of the role of these metabolic pathways in reperfusion injury and their regulation by reversible protein acetylation presents a promising way forward in improving the treatment of cardiac reperfusion injury. Here we briefly review some of what is known about how acetylation regulates mitochondrial metabolism and how it relates to I/R injury.     

Expression and Cellular Distribution of Ubiquitin in Response to Injury in the Developing Spinal Cord of Monodelphis domestica

Ubiquitin, an 8.5 kDa protein associated with the proteasome degradation pathway has been recently identified as differentially expressed in segment of cord caudal to site of injury in developing spinal cord. Here we describe ubiquitin expression and cellular distribution in spinal cord up to postnatal day P35 in control opossums (Monodelphis domestica) and in response to complete spinal transection (T10) at P7, when axonal growth through site of injury occurs, and P28 when this is no longer possible. Cords were collected 1 or 7 days after injury, with age-matched controls and segments rostral to lesion were studied. Following spinal injury ubiquitin levels (western blotting) appeared reduced compared to controls especially one day after injury at P28. In contrast, after injury mRNA expression (qRT-PCR) was slightly increased at P7 but decreased at P28. Changes in isoelectric point of separated ubiquitin indicated possible post-translational modifications. Cellular distribution demonstrated a developmental shift between earliest (P8) and latest (P35) ages examined, from a predominantly cytoplasmic immunoreactivity to a nuclear expression; staining level and shift to nuclear staining was more pronounced following injury, except 7 days after transection at P28. After injury at P7 immunostaining increased in neurons and additionally in oligodendrocytes at P28. Mass spectrometry showed two ubiquitin bands; the heavier was identified as a fusion product, likely to be an ubiquitin precursor. Apparent changes in ubiquitin expression and cellular distribution in development and response to spinal injury suggest an intricate regulatory system that modulates these responses which, when better understood, may lead to potential therapeutic targets.     

Changes in autophagy proteins in a rat model of controlled cortical impact induced brain injury

Autophagy has been implicated in several neurodegenerative diseases and recently its role in acute brain injury has received increased interest. In our study, we investigated the profiles of autophagy-linked proteins (MAP-LC3 (Atg8), beclin-1 (Atg6) and the beclin-1-binding protein, bcl-2, following controlled cortical impact injury in rats—a model for moderate-to-severe traumatic brain injury. We observed significant increases in the levels of the processed form of LC3 (LC3-II) in the ipsilateral cortex 2 h to 2 days after injury when compared to sham. Furthermore, the beclin-1/bcl-2 ratio in the ipsilateral cortex was found to have increased from 1 and 2 days after injury. Since both of these changes are established autophagy-enabling events, and, based on these data, we propose that autophagy, plays a role in the manifestation of cell injury following brain trauma.     

Progress in research on radiation combined injury in China

The significant feature of radiation combined injury is the occurrence of a combined effect. For decades our institute has focused on studying the key complications of radiation-burn injury, including shock, suppression of hematopoiesis and immunity, gastrointestinal damage and local refractory wound healing. Here we summarize recent advancements in elucidating the mechanisms of and potential treatments for radiation combined injury. Concerning the suppression and regeneration of hematopoiesis in radiation combined injury, mechanisms of megakaryocyte damage have been elucidated and a new type of fusion protein stimulating thrombopoiesis has been developed and is being tested in animals. With regard to the damage and repair of intestinal epithelium, the important molecular mechanisms of radiation combined injury have been clarified, and new measures to prevent and treat gastrointestinal tract injury are proposed. With respect to the difficulties encountered in wound healing, the underlying causes of radiation combined injury have been proposed, and some potential methods to accelerate wound closure are under study. Systemic experiments have been done to determine the appropriate time for eschar excision and skin grafting, and the results provided significant insight into clinical treatment of the injury. In the search for early therapeutic regimens for severe burns and radiation combined injury to prevent deterioration of injuries and to improve survival, cervical sympathetic ganglion block was used for the treatment of animals with radiation combined injury and had significant benefits. These research advancements have potential for application in on-site emergency rescue and in-hospital treatment of radiation combined injury.     

Development of Prolonged Focal Cerebral Edema and Regional Cation Changes Following Experimental Brain Injury in the Rat

The present study examined the formation of regional cerebral edema in adult rats subjected to lateral (parasagittal) experimental fluid-percussion brain injury. Animals receiving fluid-percussion brain injury of moderate severity over the left parietal cortex were assayed for brain water content at 6 h, 24 h, and 2, 3, 5, and 7 days post injury. Regional sodium and potassium concentrations were measured in a separate group of animals at 10 min, 1 h, 6 h, and 24 h following fluid-percussion injury. Injured parietal cortex demonstrated significant edema, beginning at 6 h post injury (p less than 0.05) and persisting up to 5 days post injury. In the hippocampus ipsilateral to the site of cortical injury, significant edema occurred as early as 1 h post injury (p less than 0.05), with resolution of water accumulation beginning at 3 days. Sodium concentrations significantly increased in both injured cortex (1 h post injury, p less than 0.05) and injured hippocampus (10 min post injury, p less than 0.05). Potassium concentrations fell significantly 1 h post injury within the injured cortex (p less than 0.05), whereas significant decreases were not observed until 24 h post injury within the injured hippocampus. Cation alterations persisted throughout the 24-h post injury period. These results demonstrate that regional brain edema and cation deregulation occur in rats subjected to lateral fluid-percussion brain injury and that these changes may persist for a prolonged period after brain injury.