New Hot Paper Comment by Miguel Che Parreira Soares

Miguel Che Parreira Soares answers a few questions about this month's new hot paper in the field of Immunology.

From •>>July 2004

Field: Immunology
Article Title: HEME OXYGENASE-1: UNLEASHING THE PROTECTIVE PROPERTIES OF HEME
Authors: Otterbein, L; Soares, MP; Yamashita, K; Bach, FH
Journal: TRENDS IMMUNOL
Volume: 24
Page: 449-455
Year: AUG 2003
* Hardvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Immunobiol Res Ctr, Boston, MA 02115 USA.
* Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Immunobiol Res Ctr, Boston, MA 02115 USA.
* Univ Pittsburgh, Montefiore Univ Hosp, Sch Med, Div Pulm & Crit Care Med, Pittsburgh, PA 15213 USA.
* Gulbenkian Inst Sci, P-2781901 Oeiras, Portugal.

Why do you think your paper is highly cited?

I believe that the manuscript is being highly cited because investigators in the field are now realizing that expression of the stress-responsive gene heme oxygenase-1 provides potent cytoprotective effects to tissues exposed to oxidative stress, such as occurs during inflammatory reactions. This notion is well supported by the pioneering work of Balla (1), Tyrrel (2) and colleagues, respectively. The fact that this information is reaching more investigators probably relates to the fact that in recent years there was an overwhelming number of reports showing that expression of heme oxygenase-1 can inhibit the pathogenesis of a broad range of inflammatory disorders/diseases, including arteriosclerosis, sepsis, rejection of transplanted organs, ischemia reperfusion, etc.

Does it describe a new discovery or new methodology that's useful to others?

There is a growing body of evidence suggesting that heme oxygenase-1 expression plays a critical role in controlling the extent of inflammatory reactions. It does so, in a manner that resolves these inflammatory reactions, preventing tissue injury and restoring homeostatic tissue function. Our review attempted to cover the cellular and molecular basis of these effects. The findings reviewed have important implications in that they unveil a broader concept, i.e., that the expression of "protective genes," such as heme oxygenase-1 can prevent the development of inflammatory disorders/diseases. Of importance as well is the possibility that modulation of the relative level of expression of these genes may be used therapeutically to suppress the pathogenesis of inflammatory disorders/diseases. In addition, our manuscript puts forward the notion that several well-recognized cytoprotective and anti-inflammatory molecules act via a common mechanism that relies on the up-regulation of heme oxygenase-1 expression. This was termed by one of my coauthors, Fritz H. Bach, as a so-called "therapeutic funnel."

Could you summarize the significance of your paper in layman's terms?

Cardiovascular and autoimmune diseases remain the most prevalent causes of disability and morbidity in the European Union and also in the United States. Our current understanding of these diseases is that they share little, if anything, in common. An alternative view, at the opposite extreme, would be to regroup these pathologic conditions under the common denominator of "inflammatory diseases." According to this notion, one would assume that they might share common features. The data described in our review suggests that the pathogenesis of these "inflammatory diseases" is modulated by the expression of "protective genes" such as the stress responsive gene heme oxygnease-1. These "protective genes" are expressed in the late phase of inflammatory reactions and contribute in a critical manner to stop inflammatory reactions. By doing so they prevent the development of chronic inflammatory lesions that can ultimately lead to "inflammatory diseases".

How did you become involved in this research?

From 1995 and 1998 I did my post-doctoral training with Fritz H. Bach at the Beth Israel Deaconess Medical Center of the Harvard Medical School. During this period we developed a series of experimental systems aimed at revealing the mechanism by which organs transplanted under a given immunosuppressive regimen became protected from the host immune response that normally lead to rejection, a phenomenon referred to as accommodation (3). We found that expression of heme oxygenase-1 in these transplanted organs was critical to prevent their rejection and establish accommodation (4). This data was the first, and so far the only direct demonstration that expression of a "protective gene", i.e., heme oxygenase-1, could prevent the rejection of a transplanted organ. These findings, which have now been confirmed in other experimental systems (reviewed in <9>), are likely to change our view of the mechanisms underlying the rejection of transplanted organs. They suggest that the mechanism that leads to the rejection of a transplanted organ is mediated not only by the relative strength of the host immune response directed against that organ but also and critically by the capacity of that organ to protect itself from injury leading to rejection. Our data shows that this protective mechanism relies on the expression of heme oxygenase-1 . We met Leo Otterbein in 1998 and become aware of his groundbreaking studies showing that carbon monoxide, the gaseous bi-product generated physiologically via the enzymatic activity of heme oxygenase-1 on heme, acted in monocyte macrophages to modulate the pro-inflammatory phenotype of these cells . We initiated a collaborative effort that lasts to this day and that lead to finding that carbon monoxide afforded the protective effect observed during the accommodation of transplanted organs . This was subsequently corroborated by the findings that carbon monoxide has potent anti-apoptotic effects , that presumably contribute to its overall protective effect in a variety of inflammatory conditions, including the rejection of transplanted organs. We then assumed that the inflammatory lesions leading to the rejection of a transplanted organ were probably not so distinct from those involved in the pathogenesis of other inflammatory disorders such as arteriosclerosis. We have shown that expression of heme oxygenase-1 and generation of carbon monoxide also suppressed the development of arteriosclerotic lesions, associated with organ transplantation and/or acute vascular injury . We found that the anti-atherogenic effect of carbon monoxide is associated not only with its potent anti-inflammatory and anti-apoptotic effects but also to its ability to suppress the proliferation of smooth muscle cells, a key event in the development of arteriosclerosis .

I have now moved my research effort to the Gulbenkian Institute of Science in Portugal where we have established a very active research team that aims to unveil the molecular mechanisms by which heme oxygenase-1 and carbon monoxide afford these protective effects.

Miguel Che Parreira Soares, Ph.D.
Associate Professor
Principal Investigator of the Inflammation laboratory
Instituto Gulbenkian de Ciencia
Oeiras, Portugal

References:

1. Balla, G., H.S. Jacob, J. Balla, M. Rosenberg, K. Nath, F. Apple, J.W. Eaton, and G.M. Vercellotti. 1992. Ferritin: a cytoprotective antioxidant strategem of endothelium. Journal of Biological Chemistry 267:18148-18153.

2. Vile, G.F., S. Basumodak, C. Waltner, and R.M. Tyrrell. 1994. Heme oxygenase mediates an adaptive response to oxidative stress in human skin fibroblasts. Proceedings of the National Academy of Sciences of the United States of America 91:2607-2610.

3. Soares, M.P., Y. Lin, K. Sato, K.M. Stuhlmeier, and F.H. Bach. 1999. Accommodation. Immunology Today 20:434-437.

4. Soares, M.P., Y. Lin, J. Anrather, E. Csizmadia, K. Takigami, K. Sato, S.T. Grey, R.B. Colvin, A.M. Choi, K.D. Poss, and F.H. Bach. 1998. Expression of heme oxygenase-1 (HO-1) can determine cardiac xenograft survival. Nature Medicine 4:1073-1077.

5. Sato, K., J. Balla, L. Otterbein, N.R. Snith, S. Brouard, Y. Lin, E. Czismadia, J. Sevigny, S.C. Robson, G. Vercellotti, A.M.K. Choi, F.H. Bach, and M.P. Soares. 2001. Carbon monoxide generated by heme oxygenase-1 suppresses the rejection of mouse to rat cardiac transplants. Journal of Immunology 166:4185-4194.

6. Katori, M., R.W. Busuttil, and J.W. Kupiec-Weglinski. 2002. Heme oxygenase-1 system in organ transplantation. Transplantation. 74:905-912.

7. Otterbein, L.E., F.H. Bach, J. Alam, M. Soares, H. Tao Lu, M. Wysk, R.J. Davis, R.A. Flavell, and A.M. Choi. 2000. Carbon monoxide has anti-inflammatory effects involving the mitogen- activated protein kinase pathway. Nat Med 6:422-428.

8. Brouard, S., L.E. Otterbein, J. Anrather, E. Tobiasch, F.H. Bach, A.M. Choi, and M.P. Soares. 2000. Carbon monoxide generated by heme oxygenase 1 suppresses endothelial cell apoptosis. J Exp Med 192:1015-1026.

9. Otterbein, L.E., M.P. Soares, K. Yamashita, and F.H. Bach. 2003. Heme oxygenase-1: unleashing the protective properties of heme. Trends in Immunology 8:449.

ESI Special Topics, July 2004
Citing URL - http://www.esi-topics.com/nhp/2004/july-04-Soares.html