title: Interleukin-11 attenuates pulmonary inflammation and vasomotor dysfunction in endotoxin-induced lung injury.
abstract: 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)-alpha 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-alpha 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-alpha 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-alpha 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-alpha 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.
authors.affiliation: Department of Surgery, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
authors.forename: B C
authors.initials: BC
authors.lastname: Sheridan
authors.forename: C A
authors.initials: CA
authors.lastname: Dinarello
authors.forename: D R
authors.initials: DR
authors.lastname: Meldrum
authors.forename: D A
authors.initials: DA
authors.lastname: Fullerton
authors.forename: C H
authors.initials: CH
authors.lastname: Selzman
authors.forename: R C
authors.initials: RC
authors.lastname: McIntyre
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D015703:Antigens, CD / Q000502:physiology; D000001:Calcimycin / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism; D050822:Cytokine Receptor gp130; D017370:Interleukin-11 / Q000494:pharmacology*; D007476:Ionophores / Q000494:pharmacology; D008070:Lipopolysaccharides; D008168:Lung / Q000737:chemistry / Q000166:cytology / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000502:physiology; D009504:Neutrophils / Q000201:enzymology / Q000276:immunology; D009599:Nitroprusside / Q000494:pharmacology; D009195:Peroxidase / Q000378:metabolism; D011014:Pneumonia / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D011652:Pulmonary Circulation / Q000187:drug effects / Q000276:immunology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I; D016019:Survival Analysis; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000276:immunology; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D015703:Antigens, CD; C494201:Il6st protein, rat; D017370:Interleukin-11; D007476:Ionophores; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha; D014665:Vasodilator Agents; D050822:Cytokine Receptor gp130; D009599:Nitroprusside; C069521:recombinant human tumor necrosis factor-binding protein-1; D000001:Calcimycin; D009195:Peroxidase; D006152:Cyclic GMP; D000109:Acetylcholine