Blunt chest trauma is involved in nearly one third of acute trauma admissions to the hospital, and lung contusion (LC) is an independent risk factor for the development of acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and ventilator-associated pneumonia (1, 2). The lung is also the second most common organ involved in blast trauma-induced LC, which often has a perihilar distribution and carries a high risk of mortality (3). When LC injury leads to hypoxemia severe enough to meet the definition of ALI/ARDS, the prognostic and economic impacts are significant. These clinical syndromes continue to have very substantial overall mortality and morbidity despite significant advances in cardiorespiratory intensive care over the past several decades (4). In a 2004 study of trauma patients, the incremental hospital cost per patient with ALI or ARDS ($36,713 or $59,633, respectively) was much higher than for patients without ALI/ARDS ($24,715) (5).
The pathophysiology of pulmonary contusion and blunt chest trauma includes inflammation, increased alveolocapillary permeability and pulmonary edema, ventilation/perfusion mismatching, increased intrapulmonary shunting, and a loss of compliance (6). A schematic showing selected pathophysiological aspects contributing to pulmonary contusion injury is given in Figure 1. Clinically, patients with pulmonary contusion display hypoxemia, hypercarbia, and increased work of breathing of varying severity and duration (1), which are treated with supplemental oxygen and mechanical ventilation as indicated. There is frequently an inconsistent correlation between the volume of lung that is grossly contused in patients and the severity of clinical respiratory failure, indicating that cellular and subcellular injury and inflammation, as well as interactions with other insults occurring at or near the time of trauma, may be involved. The current review focuses on acute inflammatory mechanisms and the role of individual cell types in the evolution of LC injury in animal models. Surfactant dysfunction in LC injury is also discussed along with potential interactions of contusion injury with secondary insults such as gastric aspiration and sepsis that commonly occur in trauma patients.
ANIMAL MODELS OF LC
Studies examining the pathophysiology and cellular/molecular mechanisms of pulmonary contusion require meaningful and reproducible animal models. Physiological models for LC injury have been developed in animal species ranging in size from rodents (rats and mice) (7-16) to larger species such as swine (17-21). Selected animal models of pulmonary contusion and their representative pathological characteristics relative to clinical features reported in retrospective studies in blunt chest trauma patients are summarized in the Table 1.
Although large animal models of pulmonary contusion have important specific applications, they also can exhibit limitations that include high mortality, high cost, open chest trauma induction, the presence of penetrating and blunt trauma, and/or the existence of substantial concomitant cardiac trauma. Large animal models of LC are also somewhat limited in mechanistic investigations because of a lack of cell- and mediator-specific molecular probes and reagents, which are much more widely available for small animals such as mice and rats. Pathophysiological studies in mice can also exploit the availability of transgenic models to probe specific gene-related effects in pulmonary contusion injury. Moreover, the use of small animal species in general requires substantially lower experimental expense than studies in large animal models. For all these reasons, a good deal of recent animal model research in the pulmonary contusion field has emphasized rodent models.
Over the course of the last 5 years, three reproducible and functional closed-chest rat and murine models of LC injury have been developed (7, 9, 11-15). The rat model of isolated bilateral LC injury developed by Raghavendran et al. (12-15) involves dropping a cylindrical weight at a well-defined energy impact level onto a mobile lexon platform positioned over the thorax to minimize associated cardiac trauma. The first murine model developed for LC injury involved a unilateral chest impact using an ultrasonic blast wave (7). Recently, Hoth et al. (9, 11) have published results in another closed-chest murine model where an electrical cortical impactor was used to deliver a target energy level producing a uniform contusion to the right lung. The development of these small closed-chest rodent models has facilitated studies elucidating the roles and importance of specific cells (e.g. neutrophils), mediators, Toll-like receptors, and surfactant dysfunction in LC injury as described in the succeeding sections.
THE ACUTE INFLAMMATORY RESPONSE IN LC INJURY
Acute lung injury in both humans and animal models is characterized by an intense inflammatory response in the pulmonary parenchyma. The innate inflammatory response triggered by direct or indirect insults to the lungs involves the recruitment of blood leukocytes, the activation of tissue macrophages, and the production of a series of different mediators, including cytokines, chemokines, oxygen radicals, arachidonic acid metabolites, and components of the complement and coagulation cascades (22, 23). Although many specifics of the inflammatory response in LC injury remain to be clarified, it is clear that physiological dysfunction in this condition is related in part to the significant acute inflammation that is present (15). As noted in the legend to Figure 1, the consequences of pulmonary inflammation in the context of LC-induced traumatic tissue injury include endothelial and epithelial cell disruption and increased alveolocapillary membrane permeability. These abnormalities in turn lead to alveolar edema, surfactant dysfunction, ventilation-perfusion mismatching, decreased lung compliance and volumes, and refractory arterial hypoxemia. This section highlights the importance of the acute inflammatory response in LC injury, with specific emphasis on the contributions of selected individual cell types and inflammatory mediators in pathogenesis.
Histopathological course of LC
Using the rodent model of bilateral LC developed in our laboratory (15), a detailed histopathological evaluation of the lung tissue at 8 min, 4 h, and 12 h postcontusion revealed diffuse areas of intra-alveolar hemorrhage with disruption of alveoli, along with interstitial hemorrhagic injury that frequently involved perihilar areas and extended to the visceral surface of the pleura. At 24 h postcontusion, atelectasis was pronounced, and there were increased numbers of leukocytes (predominantly neutrophils) within the alveoli and interstitium (Fig. 2A). At 48 h, neutrophilic infiltration continued to be prominent, and alveolar lining tissue was thickened with an increase in alveolar macrophage infiltration and cellular debris (Fig. 2B) (15). Similar histological findings in LC injury have been reported by others (9). At 7 days postcontusion, evidence of fibrosis especially around the bronchioles was also observed (15). This latter cellular feature may be related conceptually to pathology observed in the early fibroproliferative stage of human ARDS (24).
Role of neutrophils in LC
The importance of neutrophils in various forms of lung injury is well established. For example, in acid aspiration-mediated lung injury, which is considered later in terms of interactions with LC injury, neutrophils are a major contributor to airway and alveolar epithelial injury (25, 26). Neutrophil-induced lung injury is frequently oxidant-mediated and may also involve impaired alveolar fluid transport function (27). However, neutrophil accumulation within the lungs is not always associated with injury (e.g. oleic acid lung injury is not strongly neutrophil-dependent despite the presence of increased numbers of these cells in the lungs) (28). To investigate the specific importance of neutrophils in LC injury, rats were treated with intravenous Vinblastine 4 days before blunt trauma-induced contusion (15). Rats given Vinblastine were evaluated for injury at 4 and 24 h postcontusion and met a prospectively defined limit of less than 5 polymorphonuclear neutrophils per 100 leukocytes in peripheral blood smears at these times. Vinblastine-treated neutropenic rats had similar levels of albumin in bronchoalveolar lavage (BAL) at 4 h postcontusion compared with nonneutropenic rats (Fig. 3). However, closed-chest quasistatic P-V curves showed that the total lung volume at 40 cm H2O was greater in neutropenic rats than in undepleted rats at this 4-h time point (15). Moreover, at 24 h postcontusion, neutropenic rats had significantly reduced albumin concentrations in BAL compared with nonneutropenic injured rats (478 ± 154 vs. 3,601 ± 564 μg/mL; P < 0.001; Fig. 3).
The underlying mechanisms by which neutrophils contribute to increased LC injury severity are currently unclear. One potential mechanism relevant for neutrophils in other forms of acute pulmonary injury involves increased necrosis/apoptosis of cells in the alveolar epithelium (23, 29). However, increased neutrophil accumulation in the lung parenchyma and airways after LC has recently been reported by Seitz et al. (30) not to be associated with the increased apoptosis of type II cells that has been observed after blunt trauma (31). Further studies on the mechanism-based contributions of neutrophils to the pathogenesis and progression of LC injury are needed to define their role in this condition in more detail.
Role of the alveolar macrophages and peripheral blood monocytes in LC
Alveolar macrophages are considered to be primary scavengers of particulate matter that reaches the alveoli. Alveolar macrophages are also sentinel cells responsible for the recognition of antigens, and they have been implicated in the pathogenesis and/or resolution of many forms of acute pulmonary injury. For example, in sepsis-induced lung injury, the severity of protein leakage has been found to be dependent on the presence of functional alveolar macrophages and specifically on the production of iNOS by these cells (32). However, depletion of alveolar macrophages using liposome encapsulated clodronate does not prevent Fas-mediated lung injury in mice (33). The early leukocytic response in the first 24 h after LC injury is predominantly neutrophilic, but it progresses to a largely monocytic response by 48 h postcontusion (7, 15). Although specific mechanisms of macrophage activation are not well understood in LC injury, there seems to be an augmented release of Th-2 cytokines by peripheral blood monocytes at 2 h post-contusion (34). In contrast, at 24 h postcontusion, the release of cytokines from peritoneal macrophages, splenic macrophages, and splenocytes has been found to be significantly suppressed (34). Studies by Liener et al. (31) suggest that increases in alveolar macrophage numbers at 48 h after thoracic trauma may be associated with increased type II cell apoptosis, suggesting a possible mechanistic role for the alveolar macrophage in the initiation or maintenance of LC injury (see succeeding section). However, further studies on the specific time-dependent mechanistic contributions of alveolar macrophages to LC injury are needed to clarify the roles and importance of these cells in pathophysiology more fully.
Apoptosis in LC
During the past two decades, the importance of programmed cell death in the pathogenesis of ALI/ARDS and multiple organ failure has become well recognized. Two major hypotheses that have been examined in animal models of lung injury and, to a lesser degree, in humans with ALI/ARDS have been categorized as the "neutrophil hypothesis" and the "epithelial hypothesis" (35). The former hypothesis suggests that apoptosis of neutrophils is the key feature in the resolution of inflammation, and that a persistent neutrophilic response will contribute to progressive inflammatory injury. The latter hypothesis suggests that alveolar epithelial injury and subsequent epithelial apoptosis is the hallmark of the pathogenesis of ALI/ARDS (35). In actuality, neutrophil-mediated and epithelial-mediated processes involved in lung injury are not mutually exclusive, and both increased alveolar epithelial apoptosis and decreased neutrophilic apoptosis may be important in the maintenance/progression of ALI/ARDS (29).
With regard to type II pneumocyte apoptosis in particular, studies in animals and humans have reported significant lung injury-induced apoptosis and dysfunction of this important lung cell type during acute inflammatory injury of various kinds (30, 31, 36, 37). In terms of work directly relevant for LC injury, Leiner et al. (31) have reported increased alveolar epithelial apoptosis after blunt chest trauma, and Seitz et al. (30) have documented increased type II cell apoptosis at 48 h after LC injury. In this latter study, reduced type II cell numbers in animals with blast wave-induced LC were associated with elevated levels of the apoptosis markers caspase 3, caspase 8, and Fas in the remaining population of these cells. These results suggested that the extrinsic Fas-Fas ligand pathway may be involved in type II cell apoptosis in LC injury (30). However, the detailed mechanistic importance of type II cell apotosis in the maintenance, progression, or resolution of LC injury is not fully defined, and further work on this issue is needed in the future.
Toll-like receptors in LC
Because of its direct interface with the external atmosphere, the respiratory epithelium is a crucial dynamic system in the regulation of innate host defense. In addition to pathogen recognition, Toll-like receptors (TLRs) in the alveolar epithelium take part in the activation of various cytokines and acute-phase proteins (38, 39). Specific roles of TLR-2 and TLR-4 in the pathogenesis of LC have recently been highlighted in murine models of pulmonary contusion (9, 11). A study investigating LC in wild-type and TLR2(-/-) knockout mice suggested that lung injury, neutrophil accumulation in the BAL, and serum levels of keratinocyte derived cytokine (KC) were all significantly reduced at 3 h in TLR-2(−/−) mice compared with wild-type mice. However, no difference in mortality, serum levels of IL-6, or intercellular adhesion molecule 1 levels were observed between these two types of mice (9). Hoth et al. (11) have also reported studies in TLR-4(−/−) and intracellular adaptor protein knockout mice (MyD88[−/−] mice) showing that lung injury severity parameters were reduced in these animals in conjunction with diminished levels of pulmonary neutrophils and reduced serum levels of KC and IL-6. Thus, in contradiction to reported findings in hyperoxia-induced and bleomycin-induced lung injuries (38, 40), a deficiency of TLR-4 seems to be protective in LC injury. At present, the mechanisms underlying the disparate effects of TLR receptors in these various types of lung injury have not been completely elucidated.
Inflammatory mediators (cytokines, chemokines) in LC injury
All forms of inflammatory lung injury depend on cell-based actions and interactions mediated via soluble mediators, including cytokines and chemokines (4, 23, 41, 42). Cytokines involved in chemotaxis (i.e. chemokines) have a documented importance in the initiation, maintenance, and resolution of acute pulmonary injury from multiple causes (41, 42). In closed-chest LC-induced injury in rats, levels of neutrophilic CXC chemokines (cytokine-induced neutrophil chemoattractant [CINC-1/GRO/CXCL1] and macrophage inflammatory protein 2 [MIP-2]) peak in BAL at 24 h postcontusion (15) (Fig. 4). This postcontusion time point correlates with increased neutrophil accumulation in the lung parenchyma and airways, and with increased total lung myeloperoxidase activity as a marker of neutrophil activation. The concentration of the monocytic CC chemokine macrophage chemoattractant protein 1 (MCP-1/CCL2) is also found to be increased in BAL at 24 h postcontusion and remains elevated at 48 h postcontusion (15) (Fig. 4). Levels of all three of these chemokines return to baseline at 7 days postcontusion. Concentrations of IL-6 in BAL are found to be significantly elevated at 24 h postcontusion and return to baseline at 7 days. In addition, levels of the proinflammatory cytokine IL-1β in BAL are elevated at 24 to 48 h postcontusion and similarly decrease to baseline at 7 days postcontusion (15). Similar findings have also been reported in an open-chest model of LC (10).
In terms of subacute as opposed to acute pathology relevant for LC injury, bronchiolitis obliterans organizing pneumonia is characterized by the proliferation of granulation tissue within small airways and alveolar ducts (43). Fibrosis associated with bronchiolitis obliterans organizing pneumonia has been observed in rats at 7 days postcontusion (15) and has also been reported in other forms of subacute lung injury in humans (43, 44). T Cells have been implicated as important in bronchiolitis obliterans organizing pneumonia-associated fibrosis (45), and these immune cells may contribute to the pathology and resolution of isolated LC. Macrophage chemoattractant protein 1 activation of cells via the CCR2 receptor (an MCP-1 receptor) has also been implicated in the pathogenesis of granulomatous disease and bronchiolitis obliterans in lung transplant patients (46). Studies by Rosseau et al. (47) indicate that BAL levels of MCP-1 from patients with ARDS correlated with lung injury scores at 7, 14, and 21 days after the onset of ARDS. Additionally, the increased levels of MCP-1 at 7 days had a direct relationship with mortality (47). This area of mechanistic importance of MCP-1 in the initiation and maintenance of acute lung injury is actively being explored in our laboratory.
Type II cell injury and surfactant dysfunction in LC
Alveolar type II cells are the primary cell type responsible for lung surfactant production and metabolism, and are also highly important in regulating pulmonary inflammation and host defense (48). The potential importance of alveolar type II cell apoptosis in the maintenance/progression of LC injury has been detailed in an earlier section, and discussion in this section focuses on surfactant-related abnormalities. Abnormalities in surfactant composition, content, or activity have been well documented in BAL from patients with a number of forms of ALI/ARDS (49-51). Most relevant for LC injury is the study of Aufmkolk et al. (52), which reported some abnormalities in surfactant lipid composition in BAL from trauma patients. Abnormalities in lung surfactant composition or content in LC injury may in part reflect type II cell injury or dysfunction, but this has not been studied specifically to date. However, significant surfactant activity deficits associated with increased alveolar plasma protein concentrations and consistent with direct inhibitor-induced surfactant dysfunction after LC have been demonstrated (14).
The study of Raghavendran et al. (14) reported functionally important reductions in both the surface activity and percentage content of large surfactant aggregates lavaged from rats with blunt trauma-induced LC (14) (Fig. 5). The dynamic surface activity of large surfactant aggregates from rats with LC was significantly reduced in measurements on a pulsating bubble surfactometer, an instrument previously documented to assess overall surface tension lowering behavior under physical conditions directly relevant for the alveoli in vivo (37°C, 20 cycles/min, 50% surface area compression) (51). Results showed that surfactant activity deficits were most severe at 24 h postcontusion and improved toward normal over 48 to 96 h in parallel with improvements in lung injury parameters (14). Additional experiments showed that large surfactant aggregates from rats with LC had high levels of incorporated plasma protein and altered phospholipid class distributions with decreased levels of pulmonary contusion and increased levels of lysopulmonary contusion at 24 h postcontusion, consistent with direct interactions with these injury-induced inhibitors in the alveoli of injured rats (14).
The existence of surfactant dysfunction in LC injury has direct implications not only for pathophysiological understanding but also for potential therapeutic interventions using exogenous surfactant replacement to mitigate lung injury (see Refs. 49, 53-55 for reviews on surfactant therapy in ALI/ARDS). Benefits to lung function and/or survival after exogenous surfactant replacement therapy have been shown in children with ALI/ARDS (56, 57), as well as in term infants with acute respiratory failure from meconium aspiration and pneumonia (57, 58). Clinical studies of surfactant therapy in adults with ALI/ARDS have been more problematic, but this in part reflects the limitations of the specific drugs used. In particular, two surfactant drugs (Exosurf and Survanta) (51) were tested in controlled trials in adults with ARDS in the 1990s were and found to have little or no beneficial effects. However, Exosurf is now known to have very low activity and is no longer used clinically in this country. In addition, Survanta has been shown to contain minimal levels of highly active SP-B (51). Exogenous surfactants used to treat ALI/ARDS must have the maximum possible activity and inhibition resistance (49, 53-55). Infasurf, a bovine surfactant that has significant surface activity and an ability to overcome plasma protein-induced inhibition, has recently been shown to improve respiratory function and survival in pediatric patients up to 21 years of age with direct pulmonary forms of ALI/ARDS (56). Tracheal instillation of Infasurf in rats with blunt trauma-induced LC has also been shown by Raghavendran et al. (14) to improve pulmonary mechanics at 24 h postinjury, and surfactant therapy is also beneficial in swine with unilateral LC injury (59).
INTERACTIONS OF LC WITH OTHER PULMONARY INJURIES
One of the more vexing clinical aspects of blunt trauma-induced LC is that there is frequently no clear correlation between the volume of affected lung and the severity and duration of hypoxemia (1). Patients with small contusions (seen only on computed tomographic scan) may exhibit more severe hypoxemia than those with large contusions (visible on chest x-ray). Such observations are consistent with the importance of cellular and subcellular factors in the pathophysiology of LC injury, as described in previous sections. In addition, however, experiments with both rat and murine models of isolated LC indicate that hypoxia is effectively reversed by approximately 48 h (7, 15), which is not the case in a nontrivial subset of patients with this clinical diagnosis. This raises the possibility that interactions with other aspects of trauma-induced pathology may be occurring to exacerbate respiratory deficits in these individuals.
One potential contributor of this kind is gastric aspiration, which is known to be a major cause of direct pulmonary ALI/ARDS (60, 61). Patients are at increased risk for gastric aspiration at the time of trauma, particularly if they experience a brief loss of consciousness or have associated risk factors such as recent food or alcohol intake (60, 61). Many cases of gastric aspiration are unwitnessed or unreported, and aspiration pneumonitis is often a diagnosis of exclusion in patients without other known causes of respiratory compromise (60, 61). Raghavendran et al. (12) recently investigated the effects of concurrent gastric aspiration and LC in comparison to the component injuries alone. Four groups of Long-Evans rats were studied: LC alone, gastric aspiration (acid and gastric particles) alone, LC + gastric aspiration, and uninjured controls. Rats given LC + gastric aspiration had lower mean PaO2/FiO2 ratios compared with LC alone at 24 h, and higher BAL albumin concentrations compared with either LC or gastric aspiration alone (12) (Fig. 6). Rats with LC + gastric aspiration also had had more severe inflammation than rats given LC alone based on increased levels of polymorphonuclear neutrophils in BAL at 5 h, increased whole lung myeloperoxidase activity at 5 and 24 h, and increased levels of inflammatory mediators in BAL (TNF-α, IL-1β, and MCP-1 at 5 and 24 h; IL-10, MIP-2, and CINC-1 at 5 h) (12). This study concluded that concurrent gastric aspiration can exacerbate permeability lung injury and inflammation associated with LC, and that unwitnessed gastric aspiration had the potential to contribute to more severe forms of LC injury associated with ALI/ARDS and pneumonia in patients with thoracic trauma (12).
In an investigation of effects of an added septic challenge on LC injury, Perl et al. (34) reported that mortality was increased when mice were subjected to cecal ligation and puncture at 24 h after LC compared with the septic challenge alone. The authors additionally reported that severe immunosuppression evidenced by reduced cytokine production from both splenic and peritoneal macrophages after initial LC injury could have been important in the increased mortality observed when the subsequent septic challenge was added (34).
Mechanistic investigations of the inflammatory response and cellular and surfactant abnormalities after pulmonary contusion have been significantly enhanced by the establishment of reproducible small animal models. Current work has established a functional role for neutrophils in the inflammatory response contributing to LC injury, and an important aspect for future investigation involves studies aimed at defining the mechanistic importance of other cell types (e.g. alveolar epithelial cells and the alveolar macrophages) in more detail. Future work also needs to address and clarify the importance of signaling via TLR-2 and TLR-4 in LC injury and extend interpretations to other receptors such as TLR-3 and associated ligands. The roles and importance of fibroblast proliferation and the pathogenesis of fibrosis during the healing/resolution phase of inflammatory LC injury also need further study and may have broader applications for fibroproliferative ALI/ARDS and chronic lung disease outside of the trauma field. Studies examining specific interactions between pulmonary fibroblasts and alveolar epithelial cells, as well as the effects of TGF-β during LC injury progression, are examples of important aspects that could be addressed in future work of this kind. To date, there are no available data on gene expressions, proteomics, or bioinformatics with respect to LC in either human subjects or animal models. An understanding of the functional genomics for LC needs to be pursued at both animal and human levels, as comprehensively discussed for other lung diseases in this supplement (62).
On a clinical level, therapeutic strategies to improve oxygenation and alter the inflammatory response in trauma patients with LC continue to be a challenge. A few studies have suggested improvements with intravenous corticosteroids or antioxidants in animal models (63), but precise randomized studies in trauma patients have not yet been performed. Similarly, improvements in lung function with exogenous surfactants in LC have been noted in animal models (14, 59), but this has not been translated to clinical studies in patients with LC. The presence of surfactant dysfunction in LC injury provides a specific rationale for more detailed studies not only with active animal-derived surfactants such as Infasurf but also new synthetic surfactant preparations such as those containing phospholipase-resistant components (64, 65). In addition, combination therapies for lung injury that combine exogenous surfactant therapy with other interventions targeting specific aspects of inflammatory pathology are an important area for future animal model and clinical research (55). Despite recent advances in understanding inflammatory mechanisms that contribute to LC pathogenesis, mortality and morbidity remain high in patients who develop ALI/ARDS after this direct pulmonary insult. Continuing animal and clinical research to facilitate the translation of mechanism-based interventions into the realm of beneficial clinical therapies needs to be aggressively pursued.
We also greatly appreciate the assistance of Ms. Robin Kunkel with the graphics presented.
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