| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Commentaries |
From the Departments of Pathology*
and
Cellular & Structural Biology,
University of
Texas Health Science Center at San Antonio, San Antonio, Texas
Heme is a versatile molecule in nature and serves as the
prosthetic moiety for numerous hemoproteins involved in oxygen
delivery, electron transfer, and signal transduction.1
However, when left unattended, the same heme can promote free radical
formation and lipid peroxidation, resulting in cell damage and tissue
injury.2-4
Thus, a fine balance between heme synthesis
and catabolism is essential for the maintenance of cellular
homeostasis. Whereas biosynthesis of heme is catalyzed by multiple
enzymes, the only physiological mechanism of heme degradation is
through heme oxygenase (HO).1
Heme oxygenase catalyzes
breakdown of the protoporphyrin ring, producing biliverdin, carbon
monoxide, and free ferrous iron.5
To this date,
three isoforms of heme oxygenase have been identified.6
Among them, HO-1, unlike the other two (HO-2 and -3), shows limited
expression under normal situations and is induced by a variety of
physiological stimuli.5,7,8
Heme, free iron, and a number
of oxidative stressors can markedly potentiate this inductive response.
Transcriptional control of HO-1 is mediated by multiple factors
including NF
B and AP-1. Both of these transcription factors
are activated by free radicals generated by heme, iron, and other
unrelated agents.5,7-10
Then what is the biological
meaning of the specific induction? For some time, evidence has been
accumulating to suggest that HO-1 induction is an adaptive response to
cellular stresses.5,7,8
In this issue of The American Journal of Pathology, Nath et al report experiments establishing a major protective role for HO-1 induction in acute renal failure caused by heme overload, using HO-1 gene knockout mice.11 Heme overload commonly occurs when hemoglobin or myoglobin is released as a consequence of hemolysis or rhabdomyolysis. Although several cell types in the body become exposed to excessive heme when this happens, the brunt of the overload is borne by the kidney. Filtered in large amounts, heme proteins and their derivatives not only may precipitate within tubular lumina, but also may be taken up by tubular epithelium and catabolized. These events are deleterious for the kidney and commonly lead to compromised tubular integrity and impaired glomerular and tubular function, resulting in acute renal failure (ARF). This type of ARF occurs in several clinical settings, but most commonly in crush syndrome caused by severe trauma to the extremities, first identified as an entity during the aerial bombing of London during World War II.12,13 Animal models of this disease caused by intramuscular injections of glycerol or intravenous infusions of hemoproteins have yielded important information on the pathogenesis of renal injury.13 Hypovolemia/dehydration and aciduria predispose to this type of ARF by promoting the formation of heme-containing casts, which obstruct tubular lumina. In addition, vasoconstriction and attendant decrease of glomerular filtration play important causal roles in renal failure as well. Nevertheless, the cytotoxicity of heme to epithelial cells has emerged as a major factor.
Nath and his colleagues have examined the role of HO-1 in acute renal failure caused by heme/hemoprotein overload using two experimental models.11 In one model, intramuscular injection of hypertonic glycerol led to rhabdomyolysis, resulting in massive release of myoglobin from damaged muscle cells. As a result, levels of circulating heme were significantly elevated. Wild-type mice in which HO-1 was induced during the insult were able to degrade the excessive heme and sustained only mild renal insufficiency without mortality. In sharp contrast, homozygous HO-1-null mice, unable to express HO-1, developed severe renal failure with 100% mortality within 15 days of glycerol injection. Such a compelling observation was further substantiated by direct intravenous infusion of hemoglobin. Again, mutant mice without functional HO-1 gene displayed acute renal failure and marked mortality, whereas the same doses of hemoglobin were tolerated by the wild-type. Together, these results have provided clear-cut evidence of a protective role for HO-1 in ARF caused by heme or hemoprotein overload.
The finding that HO-1 induction under stressful situations is beneficial is not new. In 1992, Nath and his colleagues showed that pharmacological inhibition of HO-1 activity sensitized rat kidneys to injury.14 Moreover, exposure to large amounts of hemoproteins caused profound renal damage, whereas prior exposure of rat kidneys to subtoxic doses of hemoglobin led to the expression of HO-1 and ferritin, which conferred remarkable resistance to subsequent heme toxicity.14 In support of these observations, studies from other groups have shown that up-regulation of HO-1 through overexpression or pharmacological approaches protects a variety of cell types against injury from diverse types of insults.4,15-20 Moreover, recent experiments by Poss and Tonegawa have demonstrated that, in the absence of functional HO-1 gene, defensive ability of the cell against endotoxin is drastically reduced.21 Now, the study reported by Nath et al in this issue has further established a protective role played by HO-1 during in vivo acute renal failure.11
With incontrovertible evidence for cytoprotection by HO-1, a
tantalizing question remains only partially addressed. Could this
enzyme also play a role in the development of tissue pathology? One
important task for HO-1 is, of course, to clean up the excessive heme
released from hemoproteins under various pathological
conditions.5,8
Because free heme is a potent
cytotoxin,2-4
degradation of this molecule by HO-1
appears to be an important physiological process specially designed for
cellular detoxification. However, the actions of HO-1 seem to be far
more complex than just that. The complexity of the actions of HO-1
stems from the pleiotropic effects of end products generated during
heme catabolism (Figure 1)
. In the
biochemical reaction catalyzed by HO-1, the protoporphyrin is converted
into biliverdin, accompanied by release of carbon monoxide and
liberation of iron in the ferrous form (Fe2+).
With biliverdin reductase, biliverdin is rapidly reduced to bilirubin,
a potent physiological anti-oxidant.22
Carbon monoxide, an
emerging player in signal transduction,23
has strong
vasodilatory effects24,25
that may ameliorate
vasoconstriction and associated tissue ischemia under pathological
situations including acute renal failure. On the other hand, free iron
in the ferrous form (Fe2+) is a powerful
pro-oxidant that is used in the Fenton reaction and other processes to
facilitate free radical formation.26,27
The story does not
end here, because the antioxidant bilirubin perturbs biomembranes under
certain circumstances and becomes cytotoxic.28-30
Carbon
monoxide, a vasodilator on one hand, can poison hemoproteins on the
other.31,32
Moreover, Fe2+ is not
always bad and can induce the expression of ferritin, a well-known
cytoprotective protein that serves as an antioxidant by sequestering
iron.33,34
Whether Fe2+ liberated
from heme is harmful or not is therefore decided eventually by a
delicate balance between two factors: the amounts of
Fe2+ generated during heme catabolism, and the
availability and/or induction of apoferritin. As a matter of fact, such
a duality characterizes all of the functional aspects of HO-1. Because
the final outcome of the HO-1 action is determined by the dynamics of
heme clearance, bilirubin formation, Fe2+
release, CO generation, and ferritin induction, it is hard to predict
whether HO-1 protects cells or worsens the injury in a given situation.
Conceivably, it depends on conditions of the cell and levels of HO-1
expression. Zager et al35
have reported experiments
consistent with this line of thinking. Whereas potent renal protective
effects could be demonstrated for induced HO-1 in vivo,
acute inhibition (not induction or activation) of this enzyme exerted
protection against oxidant injury of kidney proximal tubules isolated
from rats with rhabdomyolysis. Because iron chelation by
desferrioxamine was also similarly protective, the authors suggested
that free iron liberated by HO-1 activity was a key determinant of heme
cytotoxicity. Acute inhibition of HO-1 could limit the release of free
iron from heme/hemoprotein and thus result in
cytoprotection.35
|
Thus, HO-1 induction to appropriate levels is beneficial for cell survival, whereas too much HO-1 can have opposite, adverse effects. In the experimental models of acute renal failure used by Nath et al,11 HO-1 expression was shown to be two- to fourfold of that in control, well within the protective range.36 In this context, it is prudent to re-emphasize the roles played by (heme) protein-related tubular obstruction and renal vasoconstriction in myohemoglobinuric ARF. Protection afforded by HO-1 may depend to a large extent simply on greater clearance of heme systemically by induced HO-1, and the removal of accumulating heme from tubular lumina by catabolism, thus ameliorating the severity of tubular obstruction. Moreover, by removing heme from the kidney, HO-1 may have major beneficial effects on the renal vasculature. On the one hand, generation of CO will promote vasodilation; on the other, removal of heme will result in decreased scavenging of NO by heme,37-39 increased vascular NO levels, and amelioration of vasoconstriction. In contrast, lack of the enzyme in HO-1-/- mice will lead to increasing tissue heme levels and worsen renal failure by increasing the severity of tubular obstruction and vasoconstriction. The complex interplay of the "yin and yang" of heme oxygenase and the importance of defining the context in which the enzyme is induced cannot be overstated. The bewildering duality of its eventual effects is further illustrated by the fact that heme oxygenase activity can down-regulate or inactivate nitric oxide synthase (NOS).5 For example, CO and Fe2+ produced as a result of heme oxygenase activity can inactivate NOS and decrease synthesis of the enzyme, respectively.5
In view of the demonstration by Nath et al11 that HO-1 induction during rhabdomyolysis is within the protective range,36 the question arises whether HO-1 induction is ultimately beneficial or protective in other clinically relevant circumstances. A wide range of HO-1 induction has been documented in diverse pathophysiological conditions that are potentially injurious.40-51 Therefore, to classify HO-1 simply as a protective protein seems to be an oversimplification. Nevertheless, identification of the beneficial or adverse effects of HO-1 in a given clinical setting is certainly of significance, because it holds great promise to reduce tissue pathology through manipulation of HO-1 expression using genetic or pharmacological strategies.
Footnotes
Address reprint requests to Manjeri A. Venkatachalam, M.B., B.S., Department of Pathology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229. E-mail: venkatachal{at}uthscsa.edu
Accepted for publication March 20, 2000.
References
This article has been cited by other articles:
 |
|
 |
|
  X. Liu, J. A. Simpson, K. R. Brunt, C. A. Ward, S. R. R. Hall, R. T. Kinobe, V. Barrette, M. Y. Tse, S. C. Pang, A. S. Pachori, et al. Preemptive heme oxygenase-1 gene delivery reveals reduced mortality and preservation of left ventricular function 1 yr after acute myocardial infarction Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H48 - H59. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. J. Tracz, J. P. Juncos, J. P. Grande, A. J. Croatt, A. W. Ackerman, G. Rajagopalan, K. L. Knutson, A. D. Badley, M. D. Griffin, J. Alam, et al. Renal Hemodynamic, Inflammatory, and Apoptotic Responses to Lipopolysaccharide in HO-1-/- Mice Am. J. Pathol., June 1, 2007; 170(6): 1820 - 1830. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Basireddy, J. T. Lindsay, A. Agarwal, and D. F. Balkovetz Epithelial cell polarity and hypoxia influence heme oxygenase-1 expression by heme in renal epithelial cells Am J Physiol Renal Physiol, October 1, 2006; 291(4): F790 - F795. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. M. Brusko, C. H. Wasserfall, A. Agarwal, M. H. Kapturczak, and M. A. Atkinson An Integral Role for Heme Oxygenase-1 and Carbon Monoxide in Maintaining Peripheral Tolerance by CD4+CD25+ Regulatory T Cells J. Immunol., May 1, 2005; 174(9): 5181 - 5186. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Higashimoto, H. Sakamoto, S. Hayashi, M. Sugishima, K. Fukuyama, G. Palmer, and M. Noguchi Involvement of NADP(H) in the Interaction between Heme Oxygenase-1 and Cytochrome P450 Reductase J. Biol. Chem., January 7, 2005; 280(1): 729 - 737. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. H. Kapturczak, C. Wasserfall, T. Brusko, M. Campbell-Thompson, T. M. Ellis, M. A. Atkinson, and A. Agarwal Heme Oxygenase-1 Modulates Early Inflammatory Responses: Evidence from the Heme Oxygenase-1-Deficient Mouse Am. J. Pathol., September 1, 2004; 165(3): 1045 - 1053. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L Atzori, F Chua, S E Dunsmore, D Willis, M Barbarisi, R J McAnulty, and G J Laurent Attenuation of bleomycin induced pulmonary fibrosis in mice using the heme oxygenase inhibitor Zn-deuteroporphyrin IX-2,4-bisethylene glycol Thorax, March 1, 2004; 59(3): 217 - 223. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. M. Sikorski, T. Hock, N. Hill-Kapturczak, and A. Agarwal The story so far: molecular regulation of the heme oxygenase-1 gene in renal injury Am J Physiol Renal Physiol, March 1, 2004; 286(3): F425 - F441. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Gonzalez-Michaca, G. Farrugia, A. J. Croatt, J. Alam, and K. A. Nath Heme: a determinant of life and death in renal tubular epithelial cells Am J Physiol Renal Physiol, February 1, 2004; 286(2): F370 - F377. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Tolosano, S. Fagoonee, E. Hirsch, F. G. Berger, H. Baumann, L. Silengo, and F. Altruda Enhanced splenomegaly and severe liver inflammation in haptoglobin/hemopexin double-null mice after acute hemolysis Blood, December 1, 2002; 100(12): 4201 - 4208. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. A. Nath, J. P. Grande, J. J. Haggard, A. J. Croatt, Z. S. Katusic, A. Solovey, and R. P. Hebbel Oxidative Stress and Induction of Heme Oxygenase-1 in the Kidney in Sickle Cell Disease Am. J. Pathol., March 1, 2001; 158(3): 893 - 903. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
