Alveolar macrophage depletion increases the severity of acute inflammation following nonlethal unilateral lung contusion in mice

Abstract

BACKGROUND Lung contusion (LC) is a common injury resulting from blunt thoracic trauma. LC is an important risk factor for the development acute lung injury, adult respiratory distress syndrome, and ventilator-associated pneumonia, all of which increase mortality from trauma. LC produces a nonspecific immune cellular response. Neutrophil recruitment is known to increase the severity of inflammation during LC. However, the exact role of macrophages in modulating the response to LC has not been well described. METHODS We used a cortical contusion impactor to induce unilateral LC in mice. Thoracic micro computed tomographic scans of these animals were obtained to document radiologic changes over time following LC. To understand the role of macrophages during LC, liposomal clodronate was used to deplete macrophage levels before traumatic insult. Acute inflammatory attributes after LC were assessed, by measuring pressure-volume mechanics; quantifying bronchial alveolar lavage levels of leukocytes, albumin, and cytokines; and finally examining lung specimen histopathology at 5, 24, 48, and 72 hours after injury. RESULTS After LC, alveolar macrophage numbers were significantly reduced and exhibited slowed recovery. Simultaneously, there was a significant increase in bronchial alveolar lavage neutrophil counts. The loss of macrophages could be attributed to both cellular apoptosis and necrosis. Pretreatment with clodronate increased the severity of lung inflammation as measured by worsened pulmonary compliance, increased lung permeability, amplification of neutrophil recruitment, and increases in early proinflammatory cytokine levels. CONCLUSION The presence of regulatory alveolar macrophages plays an important role in the pathogenesis of acute inflammation following LC.

Double-Stranded RNA Interacts With Toll-Like Receptor 3 in Driving the Acute Inflammatory Response Following Lung Contusion

“…One feature includes the reduction in apoptosis of the alveolar macrophage, a cell that plays a protective role in the resolution of inflammation(19), and this is a finding similar to observations in hyperoxia(29). The second mechanism involves the TLR3 driven change in polarization of the macrophage.…”

“…We have previously shown that the acute inflammatory response in LC is responsible for deficits in oxygenation and increases in quasi-static pulmonary compliance and severe permeability injury (BAL albumin)(8, 16–19). While there was a significant decrease in the BAL albumin level in TLR3 (−/−) mice (Figure 2a), pulmonary compliance and volumes were significantly lower in WT mice (Figure 2b).…”

Molecular Characterization of Hypoxic Alveolar Epithelial Cells After Lung Contusion Indicates an Important Role for HIF-1α

“…3,9,13,16,18 In the present study, we propose ODD-Luc mice as a novel model of LC. Global hypoxia developed after LC and was most pronounced in the liver and spleen.…”

“…This overall profile of inflammation and injury is consistent with that demonstrated in previous mouse and rodent models, substantiating ODD-Luc mice as a viable model for LC. 3,9,13,16,18 …”

Divergent Effects of Neutrophils on Fas-Induced Pulmonary Inflammation, Apoptosis, and Lung Damage

“…In the absence of resident AM, Fasinduced lung damage was worsened [21], displayed by significantly increased BAL protein concentration and lung histology. Furthermore, depletion of AM increased lung damage and inflammation following non-lethal unilateral lung contusion in mice [109]. The protective effects of neutrophil depletion fall into place particularly in synopsis with the exacerbation of lung injury in the absence of AM as a result of deficient phagocytosis and reduced degradation of apoptotic PMN [92].…”