Interleukin-11 attenuates pulmonary inflammation and vasomotor dysfunctionin endotoxin-induced lung injury

Interleukin (IL)-11, like other members of the gp180 receptor class, posses ses anti-inflammatory properties. We hypothesized that IL-11 pretreatment w ould attenuate endotoxin [lipopolysaccharide (LPS)]-induced lung inflammati on 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)-alpha compared wit h 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-alpha le vels (1.6 +/- 0.91 ng/g lung wet wt; P < 0.05 vs. LPS). IL-11 also diminish ed 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-alpha binding protein (175 mg/kg) attenuated LPS-induce d myeloperoxidase activity(6.04 +/- 0.14 U/g lung wet wt; P < 0.05). Both I L-11 and TNF-alpha binding protein similarly attenuated LPS-induced endothe lium-dependent vasomotor dysfunction with improved relaxation responses to 10(-7) and 10(-6) M acetylcholine and A-23187 in phenylephrine-preconstrict ed isolated pulmonary artery rings (P < 0.05 vs. LPS). Endothelium-independ ent relaxation responses to sodium nitroprusside were also improved after L PS at 10(-6) M (P < 0.05 vs. LPS). Moreover, IL-11 decreased endotoxin-indu ced mortality in CF1 mice from 90 to 50% (P less than or equal to 0.05 vs. LPS). Therefore, IL-11 prevents LPS-induced lung TNF-alpha production, neut rophil sequestration, and pulmonary vasomotor dysfunction. We conclude that IL-11 possesses antiinflammatory activity that protects against LPS-induce d lung injury and lethality.