Hemorrhagic shock initiates a systemic inflammatory response which is thought to be responsible for the development of ARDS and MOF [¹]. The pharmacological modulation of this excessive and uncontrolled release of pro-inflammatory cytokines is considered a promising therapeutic strategy [²]. Previous studies have shown that the administration of IL-10 following hemorrhagic shock is capable of reducing systemic and pulmonary inflammation [³, ⁴]. However, an early inhibition of the systemic inflammatory response may result in increased rates of infection and sepsis [⁵–¹⁰]. This concern may be diminished by immuno-modulating strategies that target hyperinflammation in specific organs, but leave systemic inflammatory responses unabated. In view of these demands, we hypothesized that inhalative administration of IL-10 following hemorrhagic shock would attenuate the pulmonary but not the systemic inflammatory response.

The immunoregulatory potential of IL-10 is well recognized and a potential role of IL-10 as a therapeutic agent is increasingly investigated in various animal models [³, ⁴, ¹²–¹⁴] and human studies [¹²]. Beneficial effects of early systemic IL-10 release following injury have been reported [³, ¹⁵], mainly related to the inhibition of proinflammatory cytokine synthesis [¹⁶, ¹⁷] and leukocyte recruitment [¹⁸]. However, especially in the later course following trauma, the incidence of infection is strongly associated with systemic IL-10 concentrations [⁵–¹⁰]. Thus, systemic IL-10 is a double-edged sword in treating severe trauma: potentially beneficial in the early but deleterious in the later phase. This conundrum raises the possibility whether locally applied IL-10 strategy could possibly protect end organs by changing their inflammatory microenvironment without altering the systemic inflammatory response and the susceptibility to infection and sepsis. The lung is frequently affected by systemic inflammation and the development of acute lung injury seems to be associated with local and systemic IL-10 concentrations, examples are hemorrhage [³, ⁴], peritonitis [¹⁹], or major surgery [²⁰]. Low IL-10 concentrations in the BAL of patients already suffering from ARDS were correlated with an increased mortality rate [²¹], whereas patients having an IL-10 polymorphism with increased IL-10 release showed a decreased incidence of ARDS [²²]. Given that hemorrhagic shock impairs the induction of IL-10 expression by alveolar macrophages [²³] and that systemic IL-10 administration attenuates pulmonary but not hepatic injury [⁴, ¹³], we hypothesized that a local repletion of pulmonary IL-10 following hemorrhagic reduces pulmonary inflammation without altering the systemic inflammatory response.

Trauma hemorrhage is well known to lead to pulmonary inflammation and leukocyte infiltration, that is at least in part mediated by KC [²⁴]. In the present study, we observed significant increases of systemic IL-6 and KC concentrations following hemorrhagic shock and both effects were not altered by inhalative IL-10 administration. These findings are in contrast to studies reporting significantly reduced systemic IL-6 and KC levels in hemorrhagic shock following intra-arterial, intraperitoneal, or subcutaneous IL-10 administration [³, ¹³, ²⁵]. These findings support our hypothesis that inhalative administered IL-10 mainly affects the lung without major alterations of the systemic inflammatory response. This is in accordance with no detectable differences of systemic IL-10 concentrations between animals subjected to hemorrhagic shock with or without inhalative IL-10, although we cannot exclude an earlier systemic IL-10 peak, due to the short half-life of IL-10.

Interestingly, we observed a significant reduction of systemic MCP-1 following inhalative IL-10 application. MCP-1 is a major attractant for macrophages and monocytes and is upregulated following trauma hemorrhage [²⁶]. An explanation for reduced systemic MCP-1 concentrations may lie in the role of alveolar macrophages which secrete MCP-1 and thereby potentiate inflammatory triggered lung injury [²⁷, ²⁸]. Thus systemic measured MCP-1 levels following hemorrhagic shock may be derived from the secretion of alveolar macrophages.

We have previously observed these specific modulations of chemokine release in a model of IL-10 KO mice [⁴]. Herein, IL-10 deficiency significantly increased systemic MCP-1 but not KC concentrations. Yet, we are not able to explain this selective modulation of chemokines by IL-10, but it may be speculated that, in contrast to the systemic MCP-1 concentration, the alveolar macrophages are not the main source for systemic measured KC levels.

The influx of inflammatory cells in the lung following hemorrhagic shock has been well described and is thought to be a major contributor to the development of remote organ dysfunction following trauma [²⁹, ³⁰]. Our data show that inhalation of IL-10 significantly reduces pulmonary myeloperoxidase activity, an established marker for pulmonary neutrophil infiltration, in shocked animals. Pulmonary histopathology showed a trend towards a decreased influx of inflammatory cells; however signs of severe pulmonary injury were not detectable in this early phase. This is in line with other studies detecting histological evidence of ARDS usually not before 24 hrs after hemorrhagic shock [⁴]. Overall, the reduced pulmonary inflammation is in accordance with other studies showing that IL-10 administration significantly decreased neutrophil infiltration in the lung [³, ³¹, ³²]. The beneficial pulmonary effect of endogenous IL-10 has also been shown in other animal models [¹³, ³³] and is further supported by clinical studies which report that nonsurvivors of ARDS had significantly lower levels of IL-10 in the BAL-fluid as compared to survivors [³⁴].

Several features and limitations of our study merit further comment. We did not investigate later time points and one may criticize that inhalative IL-10 administration may delay but not prevent pulmonary inflammation following hemorrhagic shock. Further, the unchanged systemic concentrations of IL-6, KC, and IL-10 do not rule out that other important mediators in the posttraumatic inflammatory cascade may be altered by inhalative IL-10 and thereby the susceptibility to infection may again be increased.

In conclusion, this study demonstrates that inhalative IL-10 reduces pulmonary inflammation following hemorrhagic shock without major alterations in the systemic inflammatory response. This may be a valuable therapeutic strategy because inhalative IL-10 administration may solve the dilemma of the two-edged sword: end organ protection is possible without altering the systemic inflammatory response and the susceptibility to infection and sepsis. Nonetheless, further studies are required to elucidate the complex immunomodulatory action of IL-10 under the condition of hemorrhagic shock.

This work has been supported by the Else Kröner-Fresenius-Stiftung.