Injury stimulates both systemic and mucosal immune defenses. Systemically, acute increases in TNF-α, IL-1β, IL-6, and other cytokines upregulate the acute phase protein response, the metabolic rate, mobilization of amino acids from lean tissues and immunity.28
The current work demonstrates that these pro-inflammatory cytokines regulate an acute airway mucosal immune response that requires all three cytokines to function.
The mucosal surfaces respond through both innate and specific immune defenses. The major strategic specific immune defense is secretory immunoglobulin A (sIgA), which binds to pathogens to prevent bacterial adherence and counter infection.13, 29, 30
Recently, we described the effect of injury on respiratory immune responses in humans noting significant airway IgA increases within 30 hours of serious injury. This response was reproducible in an animal model after a limited surgical stress with neck and abdominal incisions with significant increases in airway IgA at 8 hours with return to baseline by 24 hours.16
In both the human and mice, TNF-α and IL-1β significantly increase in bronchoalveolar secretions to levels significantly higher than levels in the systemic circulation suggesting a local rather than systemic-driven stress response.31
In addition, blockade of TNF-α with anti-TNF monoclonal antibodies eliminated the IgA response to injury while IL-1β blockade inhibited it.24
Because IgA prevents bacterial adherence and counters invasion by bacteria, the increase after injury is likely a protective mechanism to prevent post-injury infections. Since parenteral nutrition also inhibits this response in mice, these results are consistent with the increased incidence of pneumonia noted in seriously injured, parenterally fed trauma patients.24, 32
Transport of IgA from the lamina propria depends upon both production and transport. IL-6 causes terminal differentiation of B-cells to IgA-secreting plasma cells at mucosal sites and is one of the cytokines, along with IL-4, IL-5, and IL-10, important in stimulating IgA production.33–35
Transport of IgA is dependent upon pIgR expressed on the basement membrane of epithelial cells. pIgR molecules bind to IgA released in the lamina propria and the pIgR-IgA molecule is transported though the cell to the lumen where it is enzymatically cleaved after transport; pIgR is consumed 1:1 with the IgA molecule.18, 19
We recently showed that pIgR and IgA tissue levels in mice remain constant as luminal IgA levels increase after injury.36
This suggests an upregulation of pIgR production after injury as it is rapidly consumed during IgA transport. This likely occurs via the pro-inflammatory cytokines since TNF-α and IL-1β stimulate pIgR transcription via the NFκB pathway.20, 23, 37
This is consistent with the cytokine peaks at 3 and 8 hours in the lavage specimens.
The ‘trigger’ for this response is unclear but it does not appear to be a process driven by systemic release of cytokines. Multiple studies have described elevated plasma cytokines levels in both animals and humans after injury.6, 38
Typically, serum increases in TNF-α and IL-1β occur rapidly following injury with a lagging compensatory increase in the anti-inflammatory cytokines.28, 39
These elevations correlate with the degree of tissue injury, the degree of surgical stress, and the risk of subsequent complications.40–42
We found no early increases in serum levels of these cytokines although there is the slight possibility that they were cleared from the circulation prior to our one hour time point. This is possible because of the short serum half-life of TNF-α and IL-1β.28
This work and previous work suggests that the pulmonary response is primarily a local response.
It is clear, however, that a systemic, non-pulmonary, inflammatory response remains capable of stimulating the respiratory response since intraperitoneal administration of these 3 cytokines, but not the individual cytokines, to anesthetized animals produced a rapid pulmonary IgA response. That exogenous cytokine injection which caused increases in IgA at 2 hours may represent a difference in kinetics compared to a normal physiologic cytokine response. Still, it is unlikely that a systemic signal maintains the response since concentrations in BAL specimens were significantly higher than the serum levels and we noted a bimodal increase in BAL pro-inflammatory cytokines at times when serum levels of TNF-α and IL-1β were low or not detectable. Only IL-6 increased to significant levels in the serum in the kinetic study.
These data support the hypothesis that a localized pulmonary pro-inflammatory response explains the increases in airway IgA. The 8 hour peak of these cytokines after injury corresponds to the previously described 8 hour peak of sIgA occurring after this limited injury.16
The reason for the bimodal increase in airway TNF-α, IL-1β, and IL-6 after injury remains unclear and may be due to other inflammatory processes such as increased lung permeability, increased neutrophil accumulation, or increased myeloperoxidase activity.43, 44
Since our previous work showed that the airway response is gone by 24 hours, it seems likely that these processes would return to normal by this time.
Systemic TNF-α, IL-1β and IL-6 interact with pulmonary tissue. The pro-inflammatory cytokines, TNF-α, IL-1β, and IL-6, are involved in the localized airway response to injury. A distinct kinetic bimodal pattern occurs in airway concentrations without significant changes in serum levels of TNF-α and IL-1β. However, exogenous TNF-α, IL-1β, and IL-6 in combination replicate the post injury IgA airway increases suggesting a potential for systemic stimulation of this localized airway response.