To date, sTREM-1 has been shown to be expressed during pathogen-associated bacterial or fungal pneumonia [7
]. The role of sTREM-1 during non-infectious inflammation or trauma, however, is not well elucidated. We report here that sTREM-1 is expressed in the alveolar space during the course of non-infectious inflammation due to traumatic lung contusion. We could observe that the expression of sTREM-1 is increased until 40 hours following pulmonary contusion. The severity of lung contusion correlated well with the levels of sTREM-1 in the BAL and the functional impairment of pulmonary function following trauma.
The role of TREM-1 was initially described on neutrophils and monocytes [1
]. The authors observe that TREM is activated through lipopolysaccharides present on the surface of bacteria, and that this activation enhances an inflammatory response in an ERK1/2-depenedent and phospholipase-C-dependent fashion. The role of sTREM-1 was then further elucidated during septic shock, identifying its activating role for cytokine release. This activation was associated with an increased serum concentration of sTREM-1 in response to bacterial sepsis. This soluble form was postulated to be increased due to transcriptional activation but the increase could also be due to cleavage from the cellular surface [12
]. Furthermore, TREM-1 is known to modulate the innate response either by amplifying or dampening TLR-induced signalling [13
]. The in vitro
inhibition of TREM-1 results in reduced gene expression of the TLR4 pathway, such as the expression of CD14, myeloid differentiation protein-88, IL-10, IL-1β and monocyte chemotactic protein-1 [14
]. This inhibition was also implied during bacterial infection in a murine model of pneumococcal pneumonia. The authors postulated that sTREM-1 could hold a protective function for the healing process of the lung [15
]. TLR activation, however, is not only initiated by pathogen-associated molecular patterns but also by damage-associated molecular patterns that are released during lung contusion, such as during deceleration or blunt trauma of the lung.
To our knowledge no published data are currently available about the levels of sTREM-1 during non-infectious inflammation of the lung. Evidence about the induction of sTREM-1 in response to non-infectious pathologies was described in the blood of patients suffering from acute pancreatitis without signs of a bacterial infection [16
]. Recent work has also described that the activation of TLRs can be achieved independently of lipopolysaccharides [18
]. The activation of TLRs independent of lipopolysaccharides can result in activation of inflammatory signalling through NF-κB or hypoxia inducible factor [19
]. As an adaptive response to tissue trauma or resulting tissue hypoxia, NF-κB-dependent or hypoxia inducible factor-1a-dependent pathways might also be activated [20
]. This recently described concept could also be an explanation for non-infectious induction of TREM-1 within tissues. In line with this hypothesis, we report here an induction of sTREM-1 following lung contusion - a non-infectious entity that is associated with tissue hypoxia or TLR activation within the affected pulmonary tissue [20
The interpretations of the results of the present study are limited by several aspects. First, the sampling of BAL fluid via blind suctioning might enhance the variability of the values measured. This method is established and used in several studies for the diagnosis of ventilator-associated pneumonia [8
] and for the detection of cytokines in the BAL in the context of ventilator-associated lung injury [24
]. No data exist, however, on whether the technique of blind suctioning and the collection of samples via bronchoscopy are on a par as far as the measurements of cytokines are concerned.
Furthermore, mechanical ventilation itself stimulates inflammation [25
] and might therefore induce increased levels of sTREM-1. Increased sTREM-1 levels could also be explained by bacterial contamination or infection (that is, aspiration on scene). We therefore excluded the BALs of patients positive for intracellular organisms, bacteria or funghi. This approach might be too restrictive, however. since the detection of pathogens in the BAL does not necessarily verify pneumonia. Elevated sTREM-1 levels in the BAL could therefore be theoretically caused by the traumatic injury itself, by inflammation due to mechanical ventilation and by ventilator-associated pneumonia.
Since sTREM-1 levels in the BAL correlate to the severity of trauma, the primary cause of elevated sTREM-1 levels cannot trivially be explained by the mechanical ventilation itself, which in this study followed the same protocol for each patient irrespective of the severity of lung contusion. Furthermore, pneumonia or ventilator-associated pneumonia is not expected to already be present on the day of trauma. This allows us to exclude this reason for sTREM-1 elevation through ventilator-associated pneumonia, since by definition 48 hours of mechanical ventilation are necessary to meet the criteria for ventilator-associated pneumonia.
sTREM-1 also seems to be increased in patients bearing non-infectious processes such as peptic ulcer, inflammatory bowel disease, viral infections, malignant pleural effusions and chronic obstructive pulmonary disease, but also among patients after cardiac surgery or cardiac arrest [4
]. Most of the patients included in the study were younger than 40 years of age without relevant comorbidities. One patient anamnestically suffered from asthma bronchiale without daily medical treatment. Complications due to viral infections were not observed within the first 2 days.
Finally, the classification for severity of lung contusion by means of CT scans performed at admission to hospital, which means relatively early after the trauma, might be imprecise. Clinically the severity of lung contusion might differ from radiological visible trauma of the lung in the first hours after trauma. In our population, however, gas exchange parameters correlated negatively with the radiological classified severity of lung contusion. We therefore interpret the classification of lung contusion as a reasonably good indicator for severity of lung contusion in the population investigated.
In summary, the presented data provided evidence that sTREM-1 is expressed during non-infectious inflammation within the lung following traumatic injury. Since the subsequent healing of the lung is to date not well understood, the data from our study indicate sTREM-1 to be an interesting candidate for future investigations into a better understanding of the immunologic processes that are involved after traumatic lung contusion.