Interleukin-11 attenuates pulmonary inflammation and vasomotor dysfunction in endotoxin-induced lung injury.

Interleukin (IL)-11, like other members of the gp130 receptor class, possesses anti-inflammatory properties. We hypothesized that IL-11 pretreatment would attenuate endotoxin [lipopolysaccharide (LPS)]-induced lung inflammation and diminish injury to endothelium-dependent and -independent mechanisms of pulmonary vasorelaxation that require cGMP in Sprague-Dawley rats. LPS (20 mg/kg ip) increased lung tumor necrosis factor (TNF)-α compared with the saline control (0.7 ± 0.15 ng/g lung wet wt for control vs. 3.5 ± 0.09 ng/g lung wet wt for LPS; P < 0.05). IL-11 (200 mg/kg ip) injected 10 min before LPS administration attenuated the LPS-induced lung TNF-α levels (1.6 ± 0.91 ng/g lung wet wt; P < 0.05 vs. LPS). IL-11 also diminished LPS-induced lung neutrophil sequestration as assessed by myeloperoxidase units (2.1 ± 0.25 U/g lung wet wt for saline and 15.6 ± 2.02 U/g lung wet wt for LPS vs. 7.07 ± 1.65 U/g lung wet wt for LPS plus IL-11; P < 0.05). Similarly, TNF-α binding protein (175 mg/kg) attenuated LPS-induced myeloperoxidase activity (6.04 ± 0.14 U/g lung wet wt; P < 0.05). Both IL-11 and TNF-α binding protein similarly attenuated LPS-induced endothelium-dependent vasomotor dysfunction with improved relaxation responses to 10-7 and 10-6 M acetylcholine and A-23187 in phenylephrine-preconstricted isolated pulmonary artery rings ( P < 0.05 vs. LPS). Endothelium-independent relaxation responses to sodium nitroprusside were also improved after LPS at 10-6 M ( P < 0.05 vs. LPS). Moreover, IL-11 decreased endotoxin-induced mortality in CF1 mice from 90 to 50% ( P ≤ 0.05 vs. LPS). Therefore, IL-11 prevents LPS-induced lung TNF-α production, neutrophil sequestration, and pulmonary vasomotor dysfunction. We conclude that IL-11 possesses anti-inflammatory activity that protects against LPS-induced lung injury and lethality.