Etrolizumab is a humanised monoclonal antibody that selectively binds the β7 subunit of the heterodimeric integrins α4β7 and αEβ7. We aimed to assess etrolizumab in patients with moderately-to-severely active ulcerative colitis. In this double-blind, placebo-controlled, randomised, phase 2 study, patients with moderately-to-severely active ulcerative colitis who had not responded to conventional therapy were recruited from 40 referral centres in 11 countries. Eligible patients (aged 18-75 years; Mayo Clinic Score [MCS] of 5 of higher [or ≥6 in USA]; and disease extending 25 cm or more from anal verge) were randomised (1:1:1) to one of two dose levels of subcutaneous etrolizumab (100 mg at weeks 0, 4, and 8, with placebo at week 2; or 420 mg loading dose [LD] at week 0 followed by 300 mg at weeks 2, 4, and 8), or matching placebo. The primary endpoint was clinical remission at week 10, defined as MCS of 2 or less (with no individual subscore of >1), analysed in the modified intention-to-treat population (mITT; all randomly assigned patients who had received at least one dose of study drug, had at least one post-baseline disease-activity assessment, and had a centrally read screening endoscopic subscore of ≥2). This study is registered with ClinicalTrials.gov, number NCT01336465. Between Sept 2, 2011, and July 11, 2012, 124 patients were randomly assigned, of whom five had a endoscopic subscore of 0 or 1 and were excluded from the mITT population, leaving 39 patients in the etrolizumab 100 mg group, 39 in the etrolizumab 300 mg plus LD group, and 41 in the placebo group for the primary analyses. No patients in the placebo group had clinical remission at week 10, compared with eight (21% [95% CI 7-36]) patients in the etrolizumab 100 mg group (p=0·0040) and four (10% [0·2-24]) patients in the 300 mg plus LD group (p=0·048). Adverse events occurred in 25 (61%) of 41 patients in the etrolizumab 100 mg group (five [12%] of which were regarded as serious), 19 (48%) of 40 patients in the etrolizumab 300 mg plus LD group (two [5%] serious), and 31 (72%) of 43 patients in the placebo group (five [12%] serious). Etrolizumab was more likely to lead to clinical remission at week 10 than was placebo. Therefore, blockade of both α4β7 and αEβ7 might provide a unique therapeutic approach for the treatment of ulcerative colitis, and phase 3 studies have been planned. Genentech.

The relationship between bile duct damage and portal fibrosis in chronic liver diseases remains unclear. This study was designed to show whether human intrahepatic biliary epithelial cells can undergo epithelial–mesenchymal cell transition, thereby directly contributing to fibrogenesis. Primary human cholangiocytes were stimulated with transforming growth factor-β (TGFβ) or TGFβ-presenting T cells and examined for evidence of transition to a mesenchymal phenotype. Liver sections were labelled to detect antigens associated with biliary epithelial cells (cytokeratin 7 and 19 and E-cadherin), T cells (CD8), epithelial–mesenchymal transition (S100A4, vimentin and matrix metalloproteinase-2 (MMP-2)), myofibroblasts (α-smooth muscle actin) and intracellular signal-transduction mediated by phosphorylated (p)Smad 2/3; in situ hybridisation was performed to detect mRNA encoding TGFβ and S100A4. Stimulation of cultured cells with TGFβ induced the expression of pSmad2/3, S100A4 and α-smooth muscle actin; these cells became highly motile. Although normal bile ducts expressed ALK5 (TGFβ RI), low levels of TGFβ mRNA and nuclear pSmad2/3, they did not express S100A4, vimentin or MMP-2. However, TGFβ mRNA and nuclear pSmad2/3 were strongly expressed in damaged ducts, which also expressed S100A4, vimentin and MMP-2. Fibroblast-like cells which expressed S100A4 were present around many damaged bile ducts. Cells in the ‘ductular reaction’ expressed both epithelial and mesenchymal markers together with high levels of TGFβ mRNA and pSmad2/3. In conclusion, the cells forming small- and medium-sized bile ducts and the ductular reaction undergo EMT during chronic liver diseases, resulting in the formation of invasive fibroblasts; this process may be driven by a response to local TGFβ, possibly presented by infiltrating T cells.

The paucity of suitable lung donors and the high early mortality as the result of primary graft failure remain major challenges in pulmonary transplantation. There is evidence that the lung is injured in the donor by the process of brain death and often is made unusable or fails posttransplantation after amplification of the injury by the process of ischemia-reperfusion. An understanding of the mechanism of donor lung injury could lead to the development of new treatment strategies for the donor to reduce lung injury, increase the number of donors with acceptable lungs, and improve the results of transplantation. The pathophysiology of brain death is complex and involves sympathetic, hemodynamic, and inflammatory mechanisms that can injure the lung. The literature is reviewed, and these mechanisms are discussed together with their possible interrelations.

Ulcerative colitis (UC) is a chronic inflammatory disease of the colon. Current therapies, such as corticosteroids, immunosuppressants, and anti–tumor necrosis factor (TNF) antibodies, are not universally effective at induction and maintenance of remission,¹ x 1 Ordas, I., Eckmann, L., Talamini, M. et al. Ulcerative colitis. Lancet. 2012; 380: 1606–1619 Abstract | Full Text | Full Text PDF | PubMed | Scopus (466) | Google Scholar See all References with ≈25% of patients requiring colectomy.² x 2 Bach, S.P. and Mortensen, N.J. Ileal pouch surgery for ulcerative colitis. World J Gastroenterol. 2007; 13: 3288–3300 Crossref | PubMed | Scopus (50) | Google Scholar See all References This variable response to treatment and disease progression may reflect significant heterogeneity in disease pathobiology.³ x 3 Ananthakrishnan, A.N. Personalizing therapy for inflammatory bowel diseases. Expert Rev Gastroenterol Hepatol. 2013; 7: 549–558 Crossref | PubMed | Scopus (5) | Google Scholar See all References ^{, 4} x 4 Loftus, E.V. Jr., Davis, K.L., Wang, C.C. et al. Treatment patterns, complications, and disease relapse in a real-world population of patients with moderate-to-severe ulcerative colitis initiating immunomodulator therapy. Inflamm Bowel Dis. 2014; 20: 1361–1367 Crossref | PubMed | Scopus (2) | Google Scholar See all References Improved stratification driven by patient heterogeneity may help guide choice of therapeutic intervention and enhance efficacy and safety.

Brain-dead donors are the major source of lungs for transplantation. Brain death is characterized by two hemodynamic phases. Initially, massive sympathetic discharge results in a hypertensive crisis. This is followed by neurogenic hypotension. Up-regulation of pro-inflammatory mediators occurs in all organs and lung injury develops; this can adversely affect graft function post-transplantation. The mechanisms of the systemic and lung inflammation are unknown. We hypothesized that the hemodynamic changes are responsible for these inflammatory phenomena. Brain death was induced by intra-cranial balloon inflation in rats. This resulted in hypertensive crisis, followed by hypotension. There was a significant increase in blood neutrophil CD11b/CD18 expression and pro-inflammatory cytokine levels in serum and bronchoalveolar lavage, compared with control animals. Rupture of the capillary-alveolar membrane was demonstrated by electron microscopy. Elimination of the hypertensive response by alpha-adrenergic antagonist pre-treatment prevented inflammatory lung injury, reduced the systemic inflammatory markers and preserved capillary-alveolar membrane integrity. Correction of the neurogenic hypotension with noradrenaline ameliorated the systemic inflammatory response and improved oxygenation. We conclude that the sympathetic discharge triggers systemic and lung inflammation, which can be further enhanced by neurogenic hypotension. Management of the brain-dead donor with early anti-inflammatory treatment and vasoconstrictors is warranted.