Rockman will be new JCI Editor-in-Chief

Dr. Howard Rockman of Duke University will be the next Editor in Chief of the JCI from 2012 to 2017. The Editorial Board will be based at Duke, the University of North Carolina Chapel Hill, and Duke-NUS Graduate Medical School Singapore.  Drs. Tom Coffman and Paul Noble of Duke, Dr. Norman Sharpless from UNC, and Dr. David Virshup from Duke-NUS Singapore will serve as the Deputy Editors.

Sources:
http://www.jci.org/

FIZZ2 and lung fibrosis

A recent study by Dr. Phan and associates of Michigan identified that FIZZ2 was highly induced in lungs of rodents with bleomycin-induced pulmonary fibrosis in vivo and of human patients with idiopathic pulmonary fibrosis. FIZZ2 expression was induced in rodent and human lung epithelial cells by Th2 cytokines in vitro.

FIZZ2 deficiency significantly attenuated pulmonary fibrosis in bleomycin model.

FiZZ2 is down stream of IL-13 signaling.  It is unclear whether deletion of FIZZ2 abolishes IL-13 Th2 response.

Reference
[1] Liu, T., et al., J Immunol. 2011 May 20. [Epub ahead of print] PMID 21602491

miR-335 in stellate cell activation

An recent study suggested that miR-335 was reduced during hepatic stellate cell activation. Expression of miR-335 inhibited hepatic stellate cell migration and reduced α-SMA and collagen type I. And the authors identified tenascin-C was a target of miR-335.


Reference
[1] Chen C, et al. Loss of expression of miR-335 is implicated in hepatic stellate cell migration and activation. Exp Cell Res. 2011 May 7. [Epub ahead of print] PubMed PMID: 21586285.

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Thy-1 status correlates with fibroblast phenotype

A recent study in collaboration between Selman and Pardo from Mexico, and Hagood of UCSD examined the role of Thy-1, a GPI anchored glycoprotein, in fibroblasts from IPF. They found that Thy-1 negative fibroblasts:
1. Smaller in size;
2. Increased proliferation;
3. Enhanced migration;
4. Enhanced contration;
5. Expression of MMP9 in response to TGFbeta1.

The study is consistent with Hagood's previous reports suggesting Thy-1 negative fibroblasts represent a subset of fibroblasts with elevated activation in fibrotic lung.

Other studies suggested that fibrotic fibroblasts appear to grow slower than normal fibroblasts [2], or there is no difference in growth rate between fibrotic and normal fibroblasts [3].

References
[1] Ramírez G, Hagood JS, Sanders Y, Ramírez R, Becerril C, Segura L, Barrera L, Selman M, Pardo A. Absence of Thy-1 results in TGF-β induced MMP-9 expression and confers a profibrotic phenotype to human lung fibroblasts. Lab Invest. 2011 May 16. [Epub ahead of print] PubMed PMID: 21577212.
[2] Ramos C, Montaño M, García-Alvarez J, Ruiz V, Uhal BD, Selman M, Pardo A. Fibroblasts from idiopathic pulmonary fibrosis and normal lungs differ in growth  rate, apoptosis, and tissue inhibitor of metalloproteinases expression. Am J Respir Cell Mol Biol. 2001 May;24(5):591-8. PubMed PMID: 11350829.
[3] 1: Mio T, Nagai S, Kitaichi M, Kawatani A, Izumi T. Proliferative characteristics of fibroblast lines derived from open lung biopsy specimens of patients with IPF  (UIP). Chest. 1992 Sep;102(3):832-7. PubMed PMID: 1516411.

No EMT in lung fibrosis

In ATS 2011, a study from Dr. Brigid Hogan's laboratory suggests that mature AT2 cells appear to be capable of clonal proliferation and differentiation into Type 1 alveolar epithelial cells. However, there is no evidence that the lineage-labeled AT2 cells differentiate into mesenchymal cells using an inducible Sftpc-CreER "knock-in" mouse line in combination with a R26R-TomatoRed reporter allele. This study is against a popular hypothesis that the fibroblasts involved in the pathogenesis of IPF derive, in part, from AT2 cells, through EMT [1].

The study is consistent with other studies that did not find evidence for a contribution of EMT to kidney fibrosis [2, 3] or liver fibrosis [4, 5].


References:
[1] Barkauskas, C, et al., Lineage Tracing Of Mature Type 2 Alveolar Epithelial Cells Reveals New Insights Into Alveolar Maintenance And Repair. Am J Respir Crit Care Med 183;2011:A6347
[2] Li L, et al. Autophagy is a component of epithelial cell fate in obstructive uropathy. Am J Pathol. 2010;176(4):1767–1778.
[3] Humphreys BD, et al. Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis. Am J Pathol. 2010 Jan;176(1):85-97. Epub 2009 Dec 11. PubMed PMID: 20008127; PubMed Central PMCID:PMC2797872.
[4] Scholten D, et al. Genetic labeling does not detect epithelial-to-mesenchymal transition of cholangiocytes in liver fibrosis in mice. Gastroenterology. 2010 Sep;139(3):987-98. Epub 2010 Jun 20. PubMed PMID: 20546735; PubMed Central PMCID: PMC2930026
[5] Taura K, et al. Hepatocytes do not undergo epithelial-mesenchymal transition in liver fibrosis in mice. Hepatology. 2010 Mar;51(3):1027-36. PubMed PMID: 20052656; PubMed Central PMCID: PMC2906231.

Pirfenidone has a benifit for IPF

A new study published in Lancet online reported the results from two randomized trials that pirfenidone has a favourable benefit risk profile and represents an appropriate treatment option for patients with idiopathic pulmonary fibrosis [1]. These two trials were designed to test pirfenidone 2403 mg/day and 1197 mg/day. In one trials, high-dose pirfenidone significantly reduced the decline in % pred FVC. A consistent pirfenidone treatment effect was found up to week 48. A significant reduction in the decline from baseline to week 72 in 6MWT distance was observed in patients with pirfenidone treatment. Pirfenidone prolonged progression-free survival by 26% compared with placebo.

These trials are encouraging in gaining FDA approval use of pirfenidone in the US.

Fig 1A.

 [1] Noble PW, et al. Pirfenidone in patients with idiopathic pulmonary fibrosis
(CAPACITY): two randomised trials. Lancet. 2011 May 13. [Epub ahead of print]
PubMed PMID: 21571362.

MUC5B is a susceptible gene for IPF

A recent study by Dr. David Schwartz of University of Colorado showed that a SNP in the promoter region of MUC5B is strongly associated with FPF and IPF [1]. The odds ratios for disease among subjects who were heterozygous and those who were homozygous for the minor allele of this SNP (rs35705950) were 6.8 and 20.8, respectively, for FPF. The odds ratios for IPF were similar (9.0 and 21.8). MUC5B expression in the lung was 14.1 times as high in subjects with IPF as in those healthy donors.

The significance of the study, along with previous reports that variants in SFTPA, SFTPB, SFTPC, ABCA1, and ABCA3 were found in patients with pulmonary fibrosis, points to a plausible notion that the dysregulated secretion of lung surfactants and mucins by airway and alveolar epithelial cells leads to endoplasmic-reticulum (ER) stress. ER stress is found in alveolar epithelial cells in IPF [2]. However, we do not know the dysregulation of these proteins is duo to a common set of transcription factors or to epigenetic regulations.

[1] Seibold MA,  et al. A common MUC5B promoter polymorphism and pulmonary fibrosis. N Engl J Med. 2011 Apr 21;364(16):1503-12. PubMed PMID: 21506741.

[2] Korfei M, et al. Epithelial endoplasmic reticulum stress and apoptosis in sporadic idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2008 Oct 15;178(8):838-46. Epub 2008 Jul 17. PubMed PMID: 18635891; PubMed Central PMCID: PMC2566794.