Pulmonary Endotoxin Tolerance Protects Against Lung Injury While Maintaining Capacity To Clear Bacterial Pathogens
S Natarajan, J Kim, DG Remick. Boston University School of Medicine, Boston, MA
Background: Repeated inhalation of high doses of endotoxin, such as that contained in grain dust has been shown to cause inflammation and airflow obstruction. Endotoxin inhalation both exacerbates and protects against allergic asthma, based on the timing and dose of exposure. Sublethal endotoxin exposure induces a state of refractoriness that protects against further endotoxin challenges, termed endotoxin tolerance (E-T). Little work has been done to characterize E-T in the lung. We sought to determine whether chronic endotoxin exposure can induce a state of E-T in the lung.
Design: To induce E-T, female BALB/c mice were exposed to 1g of LPS (E.coli 011:B4) for four consecutive days by direct intratracheal installation. On day 5 mice received 10g LPS intratracheally. Control, or non-tolerant mice received PBS on days 1-4 and 10g LPS on day 5. Airways hyperresponsiveness (AHR) was measured 4 hours post final challenge. Mice were sacrificed and bronchoalveolar lavage fluid assayed for cytokines/chemokines.
Results: Chronic E-T resulted in a significant reduction in TNF, however, IL-6 was significantly increased in the tolerant group at 2 hours. Comparable CXCL1 expression was measured in both groups, however CXCL2 was significantly decreased in the E-T group.
BAL fluid mediators at 2 hours post final challenge. * denotes p<0.05 compared to Non-tolerant group
|Non-tolerant (ng/mL SEM)||Tolerant (ng/mL SEM)|
|TNF||7.7 0.8||3.4 0.3 (*)|
|IL-6||2.6 0.4||5.6 0.9 (*)|
|CXCL1||5.2 0.6||4.9 0.8|
|CXCL2||6.0 1.2||2.3 0.5 (*)|
|Tryptase||10.2 2.2||2.4 2.1 (*)|
|Cysteinyl leukotriene||0.6 0.1||2.9 1.1|
No difference was seen in the number of neutrophils in the lung between E-T and non E-T mice. AHR was significantly attenuated in E-T mice (200% above PBS) compared to non E-T mice (650% above PBS). However, cysteinyl leukotriene,and tryptase in the BAL fluid were significantly increased in E-T mice.
Conclusions: Chronic endotoxin exposure in the lung induces a specific state of immunosuppression in the context of TNF production and airways hyper-responsiveness. Other aspects of the immune response, such as IL-6 production and neutrophil recruitment remain intact. Our model also suggests that AHR is not mediated by cysteinyl leukotrienes or tryptase. Together, these data offer a possible mechanism of immune regulation that protects the lung from excessive inflammation (TNF), while retaining its ability to combat bacterial pathogens (neutrophil recruitment).
Tuesday, March 10, 2009 1:00 PM
Poster Session IV # 201, Tuesday Afternoon