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A Rat Model for Isolated Bilateral Lung Contusion from Blunt Chest Trauma

Raghavendran, Krishnan MD*†; Davidson, Bruce A. BS; Helinski, Jadwiga D. BS; Marschke, Cristi J.; Manderscheid, Patricia PhD; Woytash, James A. MD; Notter, Robert H. MD, PhD§; Knight, Paul R. MD, PhD

doi: 10.1213/01.ANE.0000180201.25746.1F
Critical Care and Trauma: Research Report

Lung contusion affects 17%–25% of adult blunt trauma patients, and is the leading cause of death from blunt thoracic injury. A small animal model for isolated bilateral lung contusion has not been developed. We induced lung contusion in anesthetized rats by dropping a 0.3-kg weight onto a precordial protective shield to direct the impact force away from the heart and toward the lungs. Lung injury was characterized as a function of chest impact energy (1.8–2.7 J) by measurements of arterial oxygenation, bronchoalveolar lavage (BAL) albumin and cytology, pressure-volume mechanics, and histopathology. Histology confirmed bilateral lung contusion without substantial cardiac muscle trauma. Rats receiving 2.7 J of chest impact energy had 33% mortality that exceeded prospectively defined limits for sublethal injury. Hypoxemia in rats with maximal sublethal injury (2.45 J) met criteria for acute lung injury at ≤24 h, improving by 48 h. BAL albumin levels were highest at ≤24 h, and remained elevated along with increased BAL leukocytes and decreased lung volumes at 48 h. We concluded that an impact energy of 2.45 J induces isolated, bilateral lung contusion and provides a useful model for future mechanistic pathophysiological assessments.

IMPLICATIONS: Lung contusion is a common problem encountered by victims of motor vehicular accidents. We have developed a rat model for lung contusion that does not involve any significant associated injury to the heart. This model will be helpful in ascertaining the complex mechanisms involved in the pathogenesis of lung contusion.

Departments of *Surgery, †Anesthesiology, and ‡Pathology, State University of New York (SUNY) at Buffalo, Buffalo; and §Department of Pediatrics, University of Rochester, Rochester, New York

This study was supported in part by National Institutes of Health Grants HL-48889 (PRK, BAD), HL69763 (PRK, BAD), and HL56176 (RHN).

Accepted for publication April 26, 2005.

Address correspondence and reprint requests to Krishnan Raghavendran, MD, Department of Surgery (Division of Trauma and Critical Care), SUNY at Buffalo, David K. Miller Building, Suite 316, 462 Grider St., Suite 316, Buffalo, NY 14215. Address e-mail to kraghave@ecmc.edu.

Lung contusion is a common problem affecting the care of trauma patients in the intensive care unit. It is the most frequently diagnosed intrathoracic injury resulting from blunt trauma, affecting 17%–25% of adult patients with this diagnosis (1,2). Lung contusion is also an independent risk factor for the development of pneumonia and severe clinical acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) (2). Clinical-pathological correlations in patients with lung contusion often show a lack of correlation between the extent of contused lung and the severity of hypoxemia (1). Patients with extensive contusions visible on conventional chest radiography may not be hypoxemic, whereas those with lung contusions small enough to be detectable only by computed axial tomography (CAT) scan can exhibit significant transient or prolonged oxygenation deficits (3). A better understanding of the pathophysiological mechanisms and cellular processes occurring in isolated lung contusion injury could significantly improve the diagnosis, prognosis, and treatment of this important condition.

Studies investigating the pathophysiology and cellular/molecular mechanisms of lung contusion require the use of meaningful, reproducible animal models. Various models for lung contusion have been developed, particularly in large animals such as canines, swine, and monkeys (4–13). Although these models have important specific applications, they also have limitations that can include frequent mortality, open chest trauma induction, the presence of penetrating as well as blunt trauma, and/or the existence of substantial concomitant cardiac trauma. Another disadvantage of large animal models of lung contusion for mechanistic investigations is the lack of molecular probes and other cell- and mediator-specific reagents, which are much more widely available for small animals such as mice and rats. Studies in small-animal species also can generally be done with greater ease and less cost compared with large-animal studies. There is currently no reliable and reproducible small-animal model for isolated bilateral lung contusion. Herein, we report a rat model of lung contusion injury caused by external blunt thoracic trauma; we examined its dependence on chest impact energy and time based on arterial oxygenation, pressure-volume (P-V) mechanics, and levels of albumin and cells in bronchoalveolar lavage (BAL). In addition, we performed histopathological assessments of lung and cardiac tissue. Results indicate that this closed-chest small-animal model will be helpful in future mechanistic studies on the pathophysiology and therapy of lung contusion.

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Methods

All procedures on rats were approved by the Institutional Animal Care and Use Committee (IACUC) at the State University of New York at Buffalo, and complied fully with state, federal, and National Institutes of Health regulations. A modified version of a previously described model of bilateral lung contusion was used (14). Lung contusion was induced in halothane-anesthetized adult male Long-Evans rats (250–300 g body weight; Harlan Sprague-Dawley, Indianapolis, IN) by dropping a hollow aluminum cylindrical weight (0.3 kg) through a vertical stainless steel tube onto a Lexon platform resting on the chest. The platform was suspended on Teflon guides to minimize friction and facilitate energy transfer to the anesthetized animal. A key feature of the model was a precordial protective shield (Plexiglas), which was attached to the undersurface of the Lexon platform and directly contacted the chest (Fig. 1). This shield protected the heart from contusion, and directed the impact energy to the lateral aspects of the chest. The xiphoid process was clearly marked on each animal, and the shield was reproducibly placed entirely on the chest without intrusion onto the neck or the abdomen. The impact energy E (in Joules, J) of the falling weight was calculated from Equation 1:

Figure 1

Figure 1

CV

CV

where m is the mass of the aluminum weight (in kilograms), g is gravitational acceleration (9.8 m/s2), and h is the height of weight above the Lexon platform (in meters). Calculations assumed that all the potential energy of the weight was transferred to the animal, neglecting frictional dissipation. The heights for the hollow cylindrical weight above the chest were calculated to generate external chest impact energies of 1.8, 2.0, 2.2, 2.45, and 2.7 J.

Arterial oxygenation (arterial partial pressure of oxygen, Pao2) was measured at 48 h in all groups, and additionally at 8 min, 4, and 24 h for animals injured with 2.45 J of impact energy. At a given time, subgroups of animals were allowed to breathe 98% O2 for 5 min (fraction of inspired oxygen [Fio2] = 0.98). Halothane anesthesia was then induced, and a midline incision made through the peritoneum. Blood (0.5 mL) was collected from the descending aorta in a heparinized syringe, followed by analysis with an ABL5 blood gas analyzer (Radiometer America, Westlake, OH).

Pulmonary P-V mechanics were measured immediately after blood samples were collected at 48 h post-contusion. A 14-gauge steel cannula was inserted into the trachea of a halothane-anesthetized rat through a 2-cm ventral midline neck incision, and was secured with a silk suture. The animal was then exsanguinated by transection of the abdominal inferior vena cava. Air was injected into the lungs at a rate of 25 mL/min by a syringe pump connected to the tracheal cannula. Inflation pressure was monitored continuously by an in-line pressure transducer connected to an Apple PowerBook G4 (Apple Computer, Cupertino, CA) equipped with a National Instruments data acquisition board (Austin, TX) and software written by the laboratory in Lab VIEW 6.0 (National Instruments). When pressure reached 40 cm H2O, the syringe pump was reversed and deflation pressures were monitored. Volumes were calculated based on the rate of injection or withdrawal, and were normalized to kilogram body weight.

After measurements of mechanics, a ventral midline incision was made through the sternum and the lung vasculature was flushed by injecting 20 mL of Hanks balanced salt solution into the beating right ventricle. BAL was then performed by alternating injection and collection of 5 × 10 mL of 37°C normal saline through the tracheal cannula. Recovered BAL fluid was centrifuged at 1500g at 4°C for 3 min to pellet cells, and the supernatant analyzed for albumin content (described below). The cell pellet was resuspended in 4 mL of phosphate-buffered normal saline + 0.1% sodium azide, and total numbers of erythrocytes (RBCs) and leukocytes (WBCs) were determined using a Multisizer 3 Coulter Counter (Beckman Coulter, Fullerton, CA). Differential cell counts were performed on cytocentrifuge preparations (Cytospin 3; Shandon Southern Instruments, Sewickley, PA) stained with Diff-Quik (Baxter, Detroit, MI).

Albumin concentrations in BAL fluid were determined by ELISA with a polyclonal rabbit anti-mouse albumin antibody (provided by Dr. Daniel Remick, University of Michigan, Ann Arbor, MI), a horseradish peroxidase-labeled goat anti-rabbit immunoglobulin G (BD Biosciences Pharmingen, San Diego, CA), and rat albumin (Sigma, St. Louis, MO) as a standard.

Histopathological evaluations were blinded and were performed by an experienced laboratory pathologist. Pulmonary and cardiac tissue were obtained from rats over a 48-h period after initial chest contusion with maximal sublethal impact energy of 2.45 J. For histological assessments of pulmonary tissue, the lungs were gradually inflated with 1% formalin, and tissue sections were stained with hematoxylin and eosin (H&E). Histological assessments of cardiac tissue also used H&E staining, and included evaluations of all four chambers of the heart in multiple sections.

Data are expressed as mean ± sem (standard error of the mean) for n animals per group. One-way ANOVA with Dunn’s post hoc test was used for intergroup pairwise comparisons. Values for correlations such as r value and P value (Fisher’s r-z test) were ascertained with the Statview software program.

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Results

Three of the 39 injured rats failed to survive (Table 1). Two of 6 rats in the 2.7-J chest impact energy group died as a result of major intrathoracic bleeding from lung lacerations, as determined at necropsy. In addition, 1 of 9 rats in the 2.2-J group died of intrathoracic bleeding from a lacerated liver without injury to the heart. All three rats that failed to survive died without waking from anesthesia immediately after the initial blunt trauma insult. Rats that received external blunt chest impact energies of 2.45, 2, and 1.8 J all survived (Table 1). Mortality in the 2.7-J impact energy group (2 of 6 animals) exceeded a 15% limit that was chosen prospectively in consultation with the IACUC to define sublethal lung contusion injury. Thus, additional experiments used 2.45 J as the maximal sublethal chest impact energy condition.

Table 1

Table 1

All surviving animals demonstrated no evidence of intrathoracic or intraabdominal bleeding or visceral injury, and radiography and physical evaluation did not reveal any associated rib fractures. In addition, injured animals exhibited normal movement, activity, and behavior in room air throughout the 48-h period after lung contusion. More detailed gross observations were made in rats injured with a chest impact energy of 2.45 J. Gross examination at death indicated that, at least superficially, both lungs were affected by contusion in a relatively uniform pattern in injured animals. Areas of contusion were acutely hemorrhagic (e.g., at 4 h). By 24 h postinjury, the contused lungs had an altered gross appearance, with prominent purplish surface discolorations. By 48 h, areas of contused lung appeared to be brownish in color. In contrast to the lungs, there was no evidence of significant cardiac trauma on gross examination.

Histological sections were examined to assess the severity of pulmonary and cardiac tissue injury in rats receiving the maximal sublethal chest impact energy of 2.45 J. At 4 h and 12 h post-contusion, pulmonary tissue showed diffuse areas of intraalveolar hemorrhage with disruption of alveoli (Fig. 2A). Perihilar tissue was also involved, with affected areas of parenchyma in many cases extending to the visceral surface of the pleura. Similar patterns of acute injury were apparent bilaterally, although quantitative morphometrics were not done. At 24 h post-contusion, a predominantly neutrophilic pattern of leukocyte infiltration was apparent in the alveolar spaces, and significant atelectasis was also observed (Fig. 2B). At 48 h, thickening of the alveolar lining with a continuing leukocytic infiltration was apparent along with intraalveolar edema (Fig. 2C). Tissue examination of all four chambers of the heart did not reveal any substantial disruption of cardiac muscle at any time (Fig. 2D–F at 12 and 24 h post-contusion).

Figure 2

Figure 2

The ratio of Pao2/Fio2 was determined at 48 h post-contusion in rats with sublethal lung contusion injury (1.8–2.45 J). Before blood sampling from the abdominal aorta, animals breathed 98% oxygen to fix Fio2 at 0.98. This brief period of high Fio2 breathing highlighted differences in hypoxemia between experimental groups, and also facilitated subsequent absorption atelectasis to standardize P-V compliance measurements. Pao2/Fio2 ratios at 48 h in rats given chest impact energies of 1.8–2.45 J were equivalent to uninjured controls (e.g., Table 2 for 2.45 J). However, Pao2/Fio2 ratios at 8 min, 4 h, and 24 h post-contusion in rats receiving the 2.45-J level of impact indicated severe acute arterial hypoxemia, with Pao2/Fio2 ratios of 109 ± 14 mm Hg at 1 h and 169 ± 25 mm Hg at 4 h after contusion (Table 2). Significant arterial hypoxemia was also evident at 24 h post-contusion in rats injured with 2.45 J of chest impact energy (Table 2).

Table 2

Table 2

Albumin levels in BAL were measured to assess permeability injury to the alveolocapillary membrane, as in previous studies of acute inflammatory lung injury (15–19). At 48 h post-contusion, injured rats showed significant energy-dependent increases in BAL albumin (r value = 0.62 and P value < 0.001 by Fisher’s r-z test) (Fig. 3). Albumin levels in BAL at 48 h post-contusion were 211 ± 53 μg/mL for rats receiving 2.45 J of chest impact energy, and 146 ± 34 μg/mL for those receiving 2.2 J, compared with 22.7 ± 3 μg/mL in controls (Fig. 3). Additional time-course studies showed that albumin levels in BAL from rats injured with 2.45 J of chest impact energy were increased to an even greater extent in the first 24 h post-contusion (Table 2). Early increases in BAL albumin levels were consistent with the severe arterial hypoxemia observed in these animals at 8 min and 4 h post-contusion (Table 2).

Figure 3

Figure 3

The cellular response in BAL varied with both chest impact energy and time. At 48 h post-contusion, the total numbers of leukocytes (WBCs) in BAL increased as chest impact energy increased (Fig. 4). Animals injured with 2.45 or 2.2 J had the most total WBCs per milliliter in BAL fluid (5.18 ± 3.89 × 107 and 3.44 ± 2.43 × 107, respectively, compared with 9.19 ± 1.13 × 106 in noninjured controls; Fig. 4). Additional studies in animals injured with 2.45 J of chest impact energy showed that the numbers of neutrophils in BAL were significantly increased at 24 h post-contusion (Table 2). Animals injured with 2.45 J of impact energy also had increased numbers of RBCs in BAL compared with uninjured controls at 8 min, 4 h, and 24 h post-contusion, but with no significant differences between values at these time points (Table 2).

Figure 4

Figure 4

Quasistatic P-V inflation/deflation measurements were done at 48 h post-contusion in rats given different levels of chest impact energy (1.8–2.45 J) (Fig. 5). Both inflation and deflation lung volumes at fixed pressures more than approximately 8 cm H2O were decreased in injured animals relative to controls. Decreases in lung volumes were most pronounced in rats injured with the two highest sublethal chest impact energies investigated (2.2 and 2.45 J) (Fig. 5).

Figure 5

Figure 5

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Discussion

This study has defined a reproducible, sublethal model of isolated bilateral lung contusion in rats induced by focused external blunt chest trauma. Rats receiving 1.8–2.7 J of external chest impact energy were examined. To develop a model that would be most applicable for future mechanistic studies on the evolution and pathophysiology of blunt trauma-induced lung contusion, an arbitrary upper limit of 15% mortality was prospectively chosen for maximal sublethal injury. This mortality limit was low to guarantee substantial numbers of survivors for lung injury assessments, whereas still allowing for some animal deaths in response to a significant blunt chest trauma. Rats injured with 2.7 J of chest impact energy had mortality exceeding this limit (Table 1), whereas rats receiving 2.45 and 2.2 J of impact energy had the most severe sublethal injury. Injured rats had no rib fractures on chest radiographs, and bilateral lung contusion was present on gross or histological examination without substantial disruption of cardiac muscle tissue (Fig. 2).

Isolated lung contusion injury was found to be dependent on time in addition to impact energy. Rats injured with 2.45 J of external chest impact energy had significantly increased levels of albumin and inflammatory leukocytes in BAL at 48 hours post-contusion (Figs. 3 and 4), as well as decreased inflation/deflation lung volumes at fixed pressure (Fig. 5). Hypoxemia had significantly improved in these injured animals at 48 hours, but time course studies for rats receiving 2.45 J of impact energy showed substantial acute reductions in Pao2/Fio2 ratios that met criteria for clinical ALI and/or ARDS at 8 minutes, 4 hours, and 24 hours (Table 2). Albumin levels in BAL from rats injured with 2.45 J of chest impact energy were significantly increased over controls at 8 minutes, 4 hours, 24 hours, and 48 hours post-contusion, with peak increases occurring at the earlier times (Table 2). Rats receiving 2.45 J of chest impact energy also had an acute inflammatory response, with increased numbers of neutrophils at 24 hours post-contusion (Table 2). This cellular response became more lymphocytic by 48 hours, consistent with a transition from an acute injury to a subacute or reparative stage. Histological analysis also confirmed the presence of neutrophils at 24 hours (Fig. 2).

Blunt chest trauma is a common problem in the care of critically ill trauma patients (20), and thoracic trauma accounts for 20%–25% of adult deaths caused by trauma (21). Lung contusion is the most frequently diagnosed intrathoracic injury resulting from blunt trauma (1,2), and is an important risk factor for the development of other conditions such as pneumonia and ALI/ARDS. Various large-animal models for lung contusion have been developed, including studies in canines, swine, and monkeys (4–13) (Table 3). In addition, a rat model of combined lung and heart contusion is available (22), and a blast-induced lung contusion model in mice has also been reported (23). The present rat model has the advantages of being specific in terms of lung contusion, and also uses an impact induction method that is highly relevant for clinical blunt thoracic trauma (e.g., as occurs in motor vehicle accidents). As described in Table 3, many of the features and responses found in our model are consistent with lung contusion injury in humans and in large-animal models.

Table 3

Table 3

One important feature of the current rat model is that it involves isolated (or at least relatively isolated) lung contusion injury without substantial cardiac or abdominal trauma. Wang et al. (22) reported an animal model of thoracic trauma without protection of the heart in which mortality was primarily associated with blunt myocardial injury (Table 3). In the present study, cardiac trauma was minimized by the use of a special platform and precordial shield that directed the energy of external blunt chest impact toward the lateral aspects of the chest and away from the heart. This approach is based on the work of Stockman and Roscher (14) in 1977, which described blunt trauma injury in rats caused by a falling weight in a related system. The current model differs from this previous model in the materials and specific design of the impact delivery apparatus and how it was positioned on the chest (e.g., positioning was relative to the marked xiphoid process to enhance reproducibility) (Table 3). Cardiac output and other variables of cardiac dysfunction were not measured in the present study, because these are not specific to blunt cardiac trauma. The hypoxemia and pulmonary hemodynamic changes (specifically acute reactive pulmonary hypertension) associated with lung injury have been shown in many animal studies to seriously affect cardiac function (13,26–28). In addition, in the present study, we examined a much more extensive range of physiological, histopathological, and BAL assessments of lung contusion injury, and also investigated its progression over time and its severity as a function of external chest impact energy (Tables 1 and 2 and Figs. 2–5).

Many current animal models of chest contusion are affected by how the injury is induced (Table 3). For example, one common method of inducing lung injury in such models involves firing an empty handgun into the ipsilateral lung after opening the thoracic cavity (7,11). This mechanism of injury induction in an opened chest is very dissimilar to that found in real-life situations, and may significantly alter the associated details of injury and inflammation. Other available models of chest contusion do involve closed thoracic trauma, but include continuing mechanical ventilation at the time of injury that can influence the specifics of pulmonary pathology (12,13). In our experiments, rats were not ventilated before, during, or after lung contusion.

In addition to incorporating a clinically relevant method of injury induction, future studies of lung injury in the rat model can also be expected to benefit from the greater availability of specific molecular probes for investigating the inflammatory response in rodents (mice, rats) compared with many large-animal species.

Our primary emphasis in this study was on defining the technical variables and basic characteristics of the rat model of isolated lung contusion rather than on detailed mechanistic investigations of pathophysiology. However, the results display several features consistent with other forms of acute inflammatory pulmonary injury in animals. Energy-dependent increases in the levels of albumin in BAL are consistent with increasing levels of acute injury to the integrity of the alveolocapillary membrane (Table 2, Fig. 4). Injury to the alveolar epithelium as well as the capillary endothelium is indicated, because albumin had to be present in the alveolar lumen to be accessible to lavage. The fact that albumin levels in BAL were greatest early in the course of injury at 1 and 4 hours post-contusion, and had begun to recover by 48 hours (Table 2), shows that substantial tearing or gross disruption of the alveolocapillary membrane did not occur in injured animals. The transient nature of the arterial hypoxemia observed in injured rats (Table 2, Fig. 3) also indicates that isolated lung contusion from blunt chest trauma is at least partly reversible.

The results in rats reported here support the paradigm that a severe but isolated lung contusion could lead to transient injury with a relatively rapid recovery. Our laboratory has previously reported that transient acute pulmonary injury in small animals also occurs in response to other insults such as the aspiration of acid (15–18). In contrast, we and others have demonstrated that a second insult to the lung (“two-hit hypothesis”) exacerbates inflammatory pulmonary injury and allows it to become progressive (29). Many patients with blunt chest trauma experience a transient clinical course with rapid recovery, whereas others exhibit disease that is severe and progressive (2,6,24,25). The latter clinical picture of profound, persistent hypoxemia may reflect lung contusion injury that is exacerbated by secondary events such as gastric aspiration that are also associated with the development of ALI/ARDS. In addition to having utility in future mechanistic studies on isolated lung contusion, the rat model reported herein could also be adapted to help investigate specific interactions between contusion injury and additional insults such as gastric aspiration.

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