Wednesday, October 22, 2014

Nominations are now being accepted for these prestigous awards...

Best Research Paper published in AJP-Lung by a Junior Investigator (sponsored by the American Physiological Society).

The American Journal of Physiology-Lung Cellular and Molecular Physiology invites nominations for the “Best original research paper published in AJP-Lung between 2s012-2014 by a junior author (Assistant Professor, Instructor, Post-doctoral fellow or graduate student.)  The nominee must be either first or senior author and in the opinion of the nominator, contributed significantly in the inception and conduct of this project.  Please submit a nomination stating the importance of this paper in the field as well as the contributions of the first author to Dr. Sadis Matalon, Editor AJP-Lung  (<>) with a copy to Ms. McEver (<>) by February 1st, 2015.  All applications will be reviewed by the Editor and Associate Editors who will chose the winner by secret ballot.  The winner will receive $500 and a certificate of appreciation at the EB 2015 meeting.

The Hermann Rahn Award for Excellence in Pulmonary Research (sponsored by Dr. Sadis Matalon)

Dr. Sadis Matalon, Editor-in-Chief of the American Journal of Physiology-Lung Cellular and Molecular Physiology, is soliciting nominations for the 2015 Hermann Rahn Awards, in honor of the 36th APS President (1963-1964), a leader in the field of respiration physiology.    The nominees must be either first or senior author in a paper published in the  American Journal of Physiology-Lung Cellular and Molecular Physiology since 2012 and must have been  a trainee (graduate student or post-doctoral fellow), or junior faculty (Instructor or Assistant Professor) when the paper was submitted.  Criteria for selection include the importance of the work to the field, the contribution of the nominee to this project and his trajectory as a research scientist. Please submit nominations by February 1st, 2015, to Dr. Sadis Matalon, ( with a copy to Ms. McEver (<>).  The three winners will receive $250 each and a certificate of appreciation at the EB 2015 meeting.

 The Usha (which means dawn in Sankrit) Awards (sponsored by D. Prakash YS)
Dr. Prakash YS, Deputy Editor of the American Journal of Physiology-Lung Cellular and Molecular Physiology, is soliciting nominations for the Usha awards. The nominee must be a promising trainee (undergraduate or graduate student, or a research fellow (<5 years since being granted the terminal degree (e.g. PhD, MD, DO, DVM), and should have contributed a 1st author abstract to the Respiration Section of the APS for presentation at the APS. Criteria for selection will include the level of excitement regarding the nominee's future, contribution by the nominee to the work, and the importance of the work to the field. Nominees are to be selected by the Respiration Section of the APS. All applications must be submitted by February 1st, 2015. The TWO winners will receive $500 and a certificate of appreciation at the EB 2015 meeting.

Monday, October 20, 2014

TG2 in Pulmonary Hypertension

Penumatsa KC, Toksoz D, Warburton RR, Hilmer AJ, Liu T, Khosla C, Comhair SA, Fanburg BL.Am J Physiol Lung Cell Mol Physiol. 2014 Oct 1;307(7):L576-85. doi: 10.1152/ajplung.00162.2014. Epub 2014 Aug 15.

Penumatsa KC, Fanburg BL.Am J Physiol Lung Cell Mol Physiol. 2014 Feb 15;306(4):L309-15. doi: 10.1152/ajplung.00321.2013. Epub 2013 Dec 27. Review.

Hello everyone,

I wanted to bring your attention to two recent papers in AJP Lung by Barry Fanburg’s group at Tufts University on tissue transglutaminase (TG2) in pulmonary hypertension (Penumatsa KC et al. AJPL Oct 1 2014 and Penumatsa and Fanburg BL AJPL Feb 14 2014). These very interesting papers highlight the role of TG2 in mediating and modulating the effects of hypoxia in the pulmonary vasculature in the context of PH. TG2 is a calcium-dependent enzyme that is expressed ubiquitously in multiple cell types including smooth muscle cells. TG2 is famous (or is it infamous?) for its role in celiac disease, but given its presence in other cell types, and its calcium dependency, there is much interest in its role in other diseases. TG2 is quite appealing in terms of both pathophysiology and a targetable mechanism given availability of blockers of this enzyme. (My personal interest in TG2 further lies in the fact that my uncle worked with Laszlo Lorand at Northwestern who was instrumental in our understanding of transglutaminases such as TG2 and factor XIII of the coagulation cascade). 

The Fanburg group has previously found that TG2 is increased by hypoxia while conversely blocking  TG2 prevents pulmonary hypertension in mouse models. The relevance to humans lies in increased serotonylated fibronectin (that results from increased TG2 activity) in patients with PH. In the Oct 1 paper, these authors explored the role of TG2 in mediating/modulating hypoxia effects on pulmonary artery smooth muscle cell proliferation (an aspect of vascular remodeling in PH that is in need of targeted therapies). Hypoxia was found to increase TG2 expression: an effect blocked by inhibition of HIF1a transcription factor. Separately, inhibition of the plasma membrane calcium sensing receptor blocked TG2 activity. The relevance of this latter mechanism lies in emerging evidence that the CaSR (also well known in other organ systems, particularly the parathyroid) is involved in vascular smooth muscle calcium regulation and cell proliferation. Furthermore, activators and inhibitors of CaSR are available (calcimimetics and calcilytics) and are probably being tested in the pulmonary artery. These types of studies (albeit in vitro) point to the complexity of interactions between calcium sensing/responsive pathways and proliferative/remodeling mechanisms in the pulmonary artery that likely contribute to the overall difficulty of alleviating structural and functional vascular changes in pulmonary hypertension. On the other hand, they are also exciting in terms of helping us understand how such interactions may play a role in other diseases that also involve both structural and functional changes at the level of smooth muscle (e.g. asthma). 

Y.S. Prakash

Friday, October 10, 2014

Calcineurin regulation of Ca2+ sparks in airway smooth muscle cells

Hope you have had a great summer. And I am certain that your summer reading list has included every issue of AJP Lung with exciting stories and thrilling science that makes you want to be an author as well!

I want to bring your attention to a recent paper by Savoia et al. (AJPL 2014, Sept 19, PMID:25239916) on calcineurin regulation of Ca2+ sparks in airway smooth muscle cells. Those of us in the smooth muscle and Ca regulation worlds have been fascinated by those tiny, localized bursts of Ca2+ that do more than just look pretty on high speed confocal imaging movies. Studies in different cell types have shown that sparks can regulate membrane potential (and thus indirectly affect intracellular Ca2+ and contractility) as well as modulate signaling intermediates in skeletal, cardiac and smooth muscles. It is now well-established that sparks represent localized sarcoplasmic Ca2+ release from groups of ryanodine receptors (RyRs), with the receptor isoform composition differing between cell types, and sometimes even within a cell. What is now being increasingly recognized is that RyR-mediated Ca2+ sparks are highly regulated in themselves, beyond the usual “Ca2+ induced Ca2+ release” mechanism that involves Ca2+ release via IP3 receptor (IP3R) that then activates RyR channels due to changes in the local Ca2+ environment. Such regulation has been shown to involve protein kinases for example.  
In the paper by Savoia et al., the authors report on a novel regulatory mechanism that is not dependent on IP3R, but involves the Ser/Thr protein phosphatase calcineurin (CaN). The authors show that CaN upregulates Ca2+ spark activity in airway smooth muscle cells and that a CaN inhibitor peptide (CAIP) can blunt sparks. Such effects are entirely intracellular, and do not involve Ca2+ influx or IP3R mediated local Ca2+ release. Importantly, CaN appears to regulate only RyR1 (the “skeletal” isoform), but not RyR2 or RyR3, when airway smooth muscle usually expresses all three isoforms. For me, the importance of this novel regulatory pathway is at least twofold. 

First, one could ask the question: what is the role of RyR1 per se in ASM Ca2+ and contractility, particularly in the context of inflammation or diseases such as asthma which show increased airway contractility? If, as some studies suggest, RyR1 is a key isoform, then CaN regulation that is specific to this isoform becomes quite significant as an avenue to modulate contractility. However, surprisingly, there is currently no information on changes in RyR expression patterns of smooth muscle in asthma, and thus points to at least one avenue for future research. 

Second, one should ask the question: what is the role of CaN in asthma? There is much interest in the use of calcineurin/NFAT modulators for atopy and allergy, particularly in the context of T-cell modulation, but there is again surprisingly, little to no information on how CaN could influence airway smooth muscle. The novel findings of Savoia et al. suggest at least one mechanism, that may then lead to further modulation of long-term consequences of altered intracellular Ca2+, including cell proliferation. 

Overall, I see the paper by Savoia et al. as a nice launchpad to start exploring the role of CaN in airway smooth muscle in the context of contractility and other functions of this cell type, particularly in the context of asthma.  

Regards, Y.S. Prakash