1 We investigated the eect of the p38 kinase inhibitor SB 203580 on airway in¯ammation induced by aerosolized lipopolysaccharide (LPS) in male Wistar rats. SB 203580 signi®cantly inhibited (ED 50 =15.8 mg kg 71) plasma levels of TNF-a in rats challenged with LPS (1.5 mg kg 71 , i.p.). 2 Aerosolized LPS induced a peak in TNF-a levels and the initiation of a neutrophilic response in bronchoalveolar lavage (BAL)¯uid at the 2 h time point. Furthermore, the 4 h time point was associated with the peak in IL-1b levels and the initial plateau of neutrophilia observed in the BAL uid. 3 SB 203580 (100 mg kg 71 ), had no eect on peak TNF-a levels or the associated neutrophilia in the BAL. Interestingly, the PDE 4 inhibitor RP 73401 (100 mg kg 71) signi®cantly reduced both TNF-a levels and neutrophilic in¯ammation. However, the BAL¯uid from rats pre-treated with either compound signi®cantly inhibited TNF-a release from cultured human monocytes 18 h after LPS treatment (83.6 and 44.5% inhibition, respectively). 4 Alternatively, SB 203580 (100 mg kg 71) produced dose-related inhibition of BAL IL-1b levels (67.5% inhibition, P50.01) and BAL neutrophilia (45.9% inhibition, P50.01) 4 h after LPS challenge. 5 P38 protein was present in lung tissue and the level of expression was not aected by LPS treatment.6 P38 kinase appears to be involved in the release of IL-1b and the sustained neutrophilic response in the BAL¯uid. This data may suggest a role for p38 inhibitors in the treatment of airway in¯ammatory diseases in which neutrophilia is a feature of the lung pathology.

Objectives Interleukin 11 (IL11) is highly upregulated in skin and lung fibroblasts from patients with systemic sclerosis (SSc). Here we tested whether IL11 is mechanistically linked with activation of human dermal fibroblasts (HDFs) from patients with SSc or controls. Methods We measured serum IL11 levels in volunteers and patients with early diffuse SSc and manipulated IL11 signalling in HDFs using gain- and loss-of-function approaches that we combined with molecular and cellular phenotyping. Results In patients with SSc, serum IL11 levels are elevated as compared to healthy controls. All transforming growth factor beta (TGFβ) isoforms induced IL11 secretion from HDFs, which highly express IL11RA and the gp130 co-receptor, suggestive of an autocrine loop of IL11 activity in HDFs. IL11 stimulated ERK activation in HDFs and resulted in HDF-to-myofibroblast transformation and extracellular matrix secretion. The pro-fibrotic action of IL11 in HDFs appeared unrelated to STAT3 activity, independent of TGFβ upregulation and was not associated with phosphorylation of SMAD2/3. Inhibition of IL11 signaling using either a neutralizing antibody against IL11 or siRNA against IL11RA reduced TGFβ-induced HDF proliferation, matrix production and cell migration, which was phenocopied by pharmacologic inhibition of ERK. Conclusions These data reveal that autocrine IL11-dependent ERK activity alone, or downstream of TGFβ stimulation, promotes fibrosis phenotypes in dermal fibroblasts and suggest IL11 as a potential therapeutic target in SSc.

No abstract

1 We investigated the ability of the cannabinoid agonists CP55,940 (CB 1 /CB 2 ) and anandamide (endogenous cannabinoid) to modulate electrical ®eld stimulation (EFS)-induced acetylcholine (ACh) release from parasympathetic nerve terminals innervating guinea-pig trachea. We assessed whether modulation of transmitter release translated to an impact on functional responses by investigating the eect of these agents on contractile responses evoked by EFS and ACh. Furthermore, we evaluated the ability of these compounds to elicit bronchodilation in precontracted guinea-pig tracheal strips. 2 CP55,940 and anandamide signi®cantly inhibited EFS-evoked ACh release (maximal inhibition of 35.1+2.9% and 33.4+6.4% at 1 mM, P50.05, respectively). The CB 1 receptor antagonist SR 141716A (1 mM), had no eect on ACh release and failed to reverse the inhibitory eect of CP55,940 (1 mM). 3 Paradoxically, CP55,940 had no signi®cant eect on EFS-evoked cholinergic contractile responses. Furthermore, CP55,940 did not relax pre-contracted tracheal strips or aect contractile responses to exogenous ACh. This lack of activity on smooth muscle tone is consistent with the fact that no detectable speci®c binding of [ 3 H] CP55,940 was found in tracheal homogenates. 4 These data suggest that cannabinoid agonists inhibit ACh release from cholinergic nerve terminals via activation of CB 2 receptors but that this inhibitory action does not impact on functional responses such as cholinergic contraction.