Lung contusion: inflammatory mechanisms and interaction with other injuries

Abstract

This article reviews current animal models and laboratory studies investigating the pathophysiology of lung contusion (LC), a common and severe condition in patients with blunt thoracic trauma. Emphasis is on studies elucidating cells, mediators, receptors, and processes important in the innate pulmonary inflammatory response that contribute to LC injury. Surfactant dysfunction in the pathogenesis of LC is also discussed, as is the potential role of epithelial cell or neutrophil apoptosis. Studies examining combination injuries where LC is exacerbated by secondary insults such as gastric aspiration in trauma patients are also noted. The need for continuing mechanism-based research to further clarify the pathophysiology of LC injury, and to define and test potential therapeutic interventions targeting specific aspects of inflammation or surfactant dysfunction to improve clinical outcomes in patients with LC, is also emphasized.

Figure 1. Schematic of selected changes in inflammation and permeability following lung contusion (LC)

The diagram depicts the onset of selected aspects of acute inflammation and permeability injury associated with blunt trauma-induced LC. Direct traumatic insult to the lungs generates an innate inflammatory response that includes the recruitment and activation of blood leukocytes, the activation of lung tissue macrophages, and the production of multiple mediators such as cytokines and chemokines. Neutrophils contribute significantly to the severity of inflammatory LC injury, and are activated at least in part via Toll-like receptors (TLRs) such as TLR 2 and 4 in the epithelium. Inflammatory mediators in LC are also released by alveolar type II cells and other resident pulmonary cells. This inflammatory response, in conjunction with direct LC-induced tissue injury, damages the barrier integrity of the alveolocapillary membrane and increases epithelial cell apoptosis/necrosis. Plasma proteins and other substances in permeability edema enter the alveoli and inactivate (inhibit) lung surfactant, exacerbating respiratory deficits. LC injury can also induce fibroblast activation and proliferation, although the mechanistic contributions of these cells to the progression of acute inflammatory injury are unclear. See text and subsequent sections for details.

Figure 2. Histopathology of tissue injury in rats with lung contusion

Panel A: Lung tissue section (10X) at 24 hr post-contusion stained with hematoxylin-eosin (H&E) showing neutrophils, edema, and red blood cells in the air spaces. Panel B: H&E-stained lung tissue section (10X) at 48 hr post-contusion showing thickening of the alveolar lining, increasing neutrophilic infiltrate and cellular debris.

Figure 3. Effects of neutrophil depletion on the severity of lung contusion injury based on albumin concentrations in bronchoalveolar lavage (BAL)

Neutrophils were depleted by intravenous Vinblastine prior to LC, and injury was severity based on BAL albumin levels was evaluated at 4 hr and 24 hr post-contusion. Neutrophil depletion significantly reduced lung injury as described in the text. Data are Mean ± SEM for N=6 at each time point.* p<0.001 compared to undepleted, contused rats.

Figure 4. Concentrations of chemokines in BAL from rats with evolving lung contusion injury

Concentrations for MIP-2, CINC-1 and MCP-1 (pg/ml) in cell-free BAL were measured by ELISA. Numbers of rats were N=9 at each time point except 12 hrs (N=7) and 7 days (N=8). Chemokine values for uninjured control rats (N = 9) were: CINC-1 (13.1 ± 1.5 pg/ml), MIP-2 (undetectable), and MCP-1 (28.0 ± 3.0 pg/ml). *P<0.001 compared to uninjured controls.

Figure 5. Content and surface activity of large surfactant aggregates in cell-free BAL from rats at various times following lung contusion (LC)

In both panels of the figure, box plots display the 25^th and 75^th quartiles of the data and the bars indicate the range. The horizontal bar within each quartile box denotes the median, and the filled square symbol the mean (n=6 rats in each group). Significant differences from specific groups are indicated by: *uninjured, ^#LC 24 hr, ^†LC 48 hr, ^§LC 72 hr. Differences were considered significant if p<0.0025 to adjust for multiple comparisons and maintain a family-wise α error <0.05. Panel A: The fraction of total BAL phospholipid that sedimented as large surfactant aggregates by centrifugation at 12,000 × g for 30 min was depleted in LC injury at all time points except 96 hr compared to controls, with the greatest decrease in large aggregate content found at 24 hr post-LC. Panel B: The minimum surface tension after 20 min of pulsation on a bubble surfactometer (37°C, 20 cycles/min, 50% area compression) was elevated in LC injury at all time points compared to uninjured controls, with the greatest elevation occurring at 24 hr post-LC.

Figure 6. Severity of lung contusion, gastric aspiration, and the combination injury of contusion plus aspiration based on albumin concentrations in BAL

Rats given lung contusion (LC), aspiration of combined acid and small gastric particles (GA), or both (LC+GA) were sacrificed at 5 or 24 hr post-injury, and concentrations of albumin in BAL were determined by ELISA (μg/ml, mean ± SEM, n = 6–11). Kruskal-Wallis (rank sum) statistical analysis was performed on data at each time point, and inter-group comparisons were made with a Bonferroni correction for multiple comparisons such that p<0.0083 was considered significant (family-wise α error = 0.05). *p<0.00001 compared to uninjured controls; ^#p<0.006 compared to LC alone; ^&p<0.00006 compared to GA alone.