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Stephen R. Walsh and Dr. Rebecca M. Baron for careful review of the manuscript. References. 1. .... Carter EP, Garat C, Imamura M. Continual emerging roles of HO-1: .... Paredi P, Leckie MJ, Horvath I, Allegra L, Kharitonov SA, Barnes PJ.
Heme Oxygenase-1: A Multifaceted Triple-Threat Molecule The Role of Heme Oxygenase-1 in Pulmonary Disease Laura E. Fredenburgh, Mark A. Perrella, and S. Alex Mitsialis Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women’s Hospital; and Division of Newborn Medicine, Children’s Hospital, Boston, Massachusetts

Heme oxygenase (HO)-1, the inducible isoform of heme oxygenase, is a cytoprotective enzyme that plays a central role in the defense against oxidative and inflammatory insults in the lung. HO-1 catalyzes the degradation of heme, a potent oxidant, into biliverdin, iron, and carbon monoxide (CO). These downstream products of heme catabolism have recently been found to mediate the antioxidant, antiapoptotic, antiproliferative, vasodilatory, and anti-inflammatory properties of HO-1. Although absence of HO-1 is rare in humans, a number of HO-1 promoter polymorphisms have been identified that may influence HO-1 expression in vivo and lead to disease states. This review will summarize studies that implicate HO-1 and heme metabolites in the pathophysiology of pulmonary disease and discuss recent advances in the therapeutic applications of HO-1. Keywords: HO-1; polymorphism; ARDS; pulmonary hypertension; COPD

CLINICAL RELEVANCE HO-1 plays a key role in the defense against oxidative and inflammatory insults in the lung. This review summarizes studies that implicate HO-1 in pulmonary disease and recent advances in the therapeutic applications of HO-1.

TNF-␣ [17–19]). HO-1 expression is upregulated in several pulmonary diseases (Table 1), including the acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), asthma, cystic fibrosis (CF), idiopathic pulmonary fibrosis (IPF), and rejection after lung transplantation (20–25).

ACUTE RESPIRATORY DISTRESS SYNDROME/ACUTE LUNG INJURY THE ROLE OF HEME OXYGENASE-1 IN PULMONARY DISEASE Heme oxygenase (HO)-1, the inducible isoform of heme oxygenase, plays a critical role in defending the lung against inflammatory and oxidant-induced cellular and tissue injury. This cytoprotective enzyme catalyzes the degradation of heme, a potent oxidant, to generate biliverdin-IX␣, iron, and carbon monoxide (CO) (Figure 1) (1). Biliverdin-IX␣ is converted to bilirubinIX␣, a potent endogenous antioxidant (2), with recently recognized anti-inflammatory properties (3), while iron is sequestered by ferritin, leading to additional antioxidant (4) and antiapoptotic (5) effects. CO has numerous biological functions, including anti-inflammatory properties (6, 7), and shares many similarities with nitric oxide (NO), such as its ability to inhibit smooth muscle cell proliferation (8, 9) and platelet aggregation (10), as well as modulate vascular tone by increasing cGMP levels (11). In the lung, HO-1 is expressed in various cells types, including type II pneumocytes and alveolar macrophages, and is induced by heme (12), hypoxia (13, 14), hyperoxia (15), and NO (16), as well as endotoxin and proinflammatory cytokines (e.g., IL-6,

(Received in final form September 3, 2006 ) This work was funded by T32 HL007633-21 (L.E.F.), RO1 HL60788 (M.A.P.), and R01 HL55454 (S.A.M.) from the National Institutes of Health. Correspondence and requests for reprints should be addressed to Laura E. Fredenburgh, Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115. E-mail: lfredenburgh@ partners.org Am J Respir Cell Mol Biol Vol 36. pp 158–165, 2007 Originally Published in Press as DOI: 10.1165/rcmb.2006-0331TR on September 15, 2006 Internet address: www.atsjournals.org

HO-1 plays a vital role in defense against oxidant-induced lung injury during ARDS. Increased HO-1 expression has been demonstrated in lung tissue and bronchoalveolar lavage (BAL) fluid from patients with ARDS (22). In addition, several murine models of lung injury have demonstrated a protective role for HO-1. Poss and Tonegawa demonstrated that embryonic fibroblasts isolated from HO-1–deficient (HO-1–/–) mice exhibited increased susceptibility to oxidative stress (26), while Lee and coworkers showed that overexpression of HO-1 in human pulmonary epithelial cells conferred resistance to hyperoxia (27). Cells stably transfected with a full-length rat HO-1 cDNA had increased viability during hyperoxic exposure that was abrogated by administration of tin protoporphyrin (SnPP), an HO inhibitor (27). Similarly, Suttner and colleagues reported that transient overexpression of HO-1 in a rat fetal lung cell line mitigated the effects of hyperoxia (28). In vivo, exogeneous administration of HO-1 to rats via a recombinant adenovirus expressing HO-1 significantly attenuated hyperoxia-induced acute lung injury (29). Rats overexpressing HO-1 in their lungs had a reduction in pulmonary edema, parenchymal inflammation, and apoptosis after hyperoxia (29). Taylor and coworkers also reported that HO-1 induction in the lung protects against hyperoxia-induced lung injury, but attributed these beneficial effects to ferritin, a byproduct of HO-1 enzyme activity (30). In contrast, Dennery and colleagues recently demonstrated that HO-1–/– mice were surprisingly resistant to hyperoxia and that adenoviral overexpression of HO-1 in HO-1–/– mice worsened lung injury (31). The authors suggested that these effects may have been mediated via iron and hydrogen peroxide (31). In addition, HO-1 has been shown to mediate protective effects in murine models of ischemia-reperfusion and endotoxemiainduced lung injury. Fujita and coworkers demonstrated that

HO-1 Series

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Figure 1. Degradation of heme by HO-1. HO-1 catalyzes heme degradation to biliverdin-IX␣, CO, and iron. These metabolites mediate the antiapoptotic, anti-inflammatory, vasodilatory, anticoagulant, antioxidant, and antiproliferative properties of HO-1.

mice deficient in HO-1 have increased mortality after lung ischemia, but could be rescued by CO administration (32). More recently, Zhang and colleagues showed that gene silencing with HO-1 siRNA worsened apoptosis of pulmonary artery endothelial cells after anoxia-reoxygenation and increased apoptosis in the lungs of mice after ischemia-reperfusion (33). Overexpression of exogeneous HO-1 attenuated apoptosis in both in vitro and in vivo models (33).

In an endotoxemia-induced lung injury model, HO-1– deficient mice develop increased end-organ damage and have increased mortality after intraperitoneal administration of LPS (19, 26). Induction of HO-1 by hemoglobin administration attenuates hypotension, end-organ dysfunction, and inflammation within the lung, and improves survival during endotoxemia (12, 34). Similarly, biliverdin administration to rats decreases lung inflammation and proinflammatory cytokine production, and

TABLE 1. OUTCOMES OF HEME OXYGENASE-1 MODULATION IN MODELS OF PULMONARY DISEASES Disease ARDS/ALI Hyperoxia-induced lung injury (rat) Hyperoxia-induced lung injury (rat) Hyperoxia-induced lung injury (mouse) Lung ischemia-reperfusion (mouse) Lung ischemia-reperfusion (mouse) Endotoxemia-induced lung injury (rat) Endotoxemia-induced lung injury (rat)

Intervention HO-1 adenovirus HO-1 induction by hemoglobin HO-1 adenovirus CO HO-1 siRNA HO-1 induction by hemoglobin Biliverdin

Endotoxemia-induced lung injury (mouse) Nebulized LPS-induced lung injury (mouse) Pulmonary hypertension Hypoxia-induced pulmonary hypertension (rat) Hypoxia-induced pulmonary hypertension (mouse)

SPC–HO-1 transgenic mice HO-1–deficient mice

Monocrotaline-induced pulmonary hypertension (rat) Asthma Ovalbumin-sensitization (guinea pig) Ovalbumin-sensitization (mouse) COPD Pancreatic elastase (mouse) Pulmonary fibrosis Bleomycin-induced pulmonary fibrosis (mouse) Bleomycin-induced pulmonary fibrosis (gld/gld mouse) Bleomycin-induced pulmonary fibrosis (mouse) Bleomycin-induced pulmonary fibrosis (rat) Bronchiolitis obliterans Heterotopic tracheal transplant-related obliterative bronchiolitis (mouse) Orthotopic lung transplantation (rat) Tracheal transplantation (mouse)

HO-1 agonists SPC–HO-1 transgenic mice

Effects Decreased inflammation and apoptosis Decreased lung injury Increased oxidative injury Improved survival, decreased fibrin, decreased PAI-1 induction Increased apoptosis Decreased inflammation, improved survival Decreased inflammation and pro-inflammatory cytokines, increased IL-10 Decreased MIP-2 in BAL Severe physiologic lung dysfunction, marked SP-B reduction

Reference 29 30 31 32 33 12, 34 3 35 36

HO inducers

Prevented pulmonary hypertension and vascular remodeling Decreased inflammation and proinflammatory cytokines, decreased pulmonary hypertension and remodeling Protected against pulmonary hypertension

39

HO induction by hemin CO

Decreased airway inflammation and hyperresponsiveness Decreased airway inflammation and hyperresponsiveness

48 49

HO-1 adenovirus

Decreased inflammation and proinflammatory cytokines, increased IL-10, attenuated airspace enlargement

54

HO inhibitor

Decreased inflammation, decreased collagen deposition, decreased TGF-␤ in BAL Decreased inflammation and fibrosis, decreased apoptosis Decreased fibrosis, decreased fibroblast proliferation in vitro Improved mortality, decreased inflammation and fibrosis, decreased TGF-␤ in BAL

59

HO-1 adenovirus CO Bilirubin

13 14

60 21 61

HO-1–deficient mice

Accelerated development of airway rejection

67

CO

Decreased inflammation and proinflammatory cytokines, decreased apoptosis Decreased luminal occlusion of graft

68

CO and CoPP

69

Definition of abbreviations: BAL, bronchoalveolar lavage; CO, carbon monoxide; CoPD, chronic obstructive pulmonary disease; CoPP, cobalt protoporphyrin; gld/gld, homozygous for Fas Ligand mutation; HO-1, heme oxygenase-1; MIP-2, macrophage inflammatory protein-2; PAI-1, plasminogen activator inhibitor-1; SPC, surfactant protein C; TGF-␤, transforming growth factor-␤.

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improves survival after LPS administration (3). In addition to its well-recognized antioxidant effects, HO-1 has emerged as an important modulator of inflammation within the lung. Overexpression of HO-1 in macrophages inhibits granulocyte macrophagecolony-stimulating factor (GM-CSF) production and reduces TNF-␣ (7) secretion in response to LPS stimulation (6). Furthermore, transgenic mice overexpressing HO-1 in the lung epithelium have reduced levels of macrophage inflammatory protein (MIP)-2 in BAL fluid during endotoxemia (35). In addition to its antioxidant and anti-inflammatory effects, recent data suggest that HO-1 may modulate surfactant protein B (SP-B) expression during ARDS (36). In a nebulizedendotoxin–induced ALI model, HO-1–deficient mice developed severe physiologic lung dysfunction that correlated with a marked reduction in SP-B levels (36). Using bone marrow transplantation to generate mice chimeric for HO-1, it was demonstrated that wild-type (WT)→HO-1–/– mice (WT donor cells into recipient HO-1–/– mice) developed significant lung dysfunction and enhanced SP-B down-regulation compared with HO1–/–→WT mice (HO-1–/– donor cells into recipient WT mice). Thus, absence of HO-1 in the lung parenchyma, not in bone marrow–derived inflammatory cells, was responsible for the development of lung injury. This suggests that parenchymal cell expression of endogenous HO-1 plays a critical role in modulating SP-B expression and the development of ALI (36). Protective effects of CO in lung injury have also been demonstrated and are reviewed separately in this series (37).

PULMONARY VASCULAR DISEASE Animal models of pulmonary hypertension suggest that HO-1 plays an important role in modulating the development of pulmonary hypertension. Absence of HO-1 is detrimental with the development of right ventricular (RV) dilation, RV infarcts, and mural thrombi after chronic hypoxic exposure (38). Endogenous overexpression of HO-1 using agonists of HO-1 prevents the development of hypoxia-induced pulmonary hypertension and vascular remodeling in the rat (13), while selective overexpression of HO-1 in the pulmonary epithelium of mice attenuates hypoxia-induced pulmonary inflammation and pulmonary hypertension (14). Similarly, in a monocrotaline model of pulmonary hypertension, HO-1 mediates the protective effects of rapamycin (39) and inhibition of HO-1 exacerbates pulmonary inflammation and RV hypertrophy (40). The exact mechanism by which HO-1 mediates protection against pulmonary vascular disease has not yet been fully elucidated. In addition to the beneficial vasodilatory and antiproliferative effects of CO which are reviewed separately (37), overexpression of HO-1 protects against apoptosis in several cell types (33) and attenuates proliferation of vascular smooth muscle cells (41). Similarly, in a femoral artery injury model, overexpression of HO-1 inhibited arterial remodeling of injured vessels by reducing cellular proliferation (42).

ASTHMA Accumulating evidence suggests that HO-1 may play a role in asthma and allergic airway inflammation. Several groups have reported increased HO-1 expression in the airways of patients with asthma (43), although Lim and coworkers found no difference in HO-1 expression in a group of subjects with mild asthma compared with control subjects (44). In addition, exhaled CO levels are elevated in individuals with asthma (43), and while some studies have shown an increase upon allergen challenge (45) and a decrease with corticosteroids (46), other studies have shown no effect (44). In a murine model of asthma, HO-1 expres-

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sion is increased in the airway lumen and bronchial submucosa of antigen-challenged mice (47). In addition, Almolki and colleagues recently demonstrated that up-regulation of HO-1 by hemin decreased airway inflammation, mucus secretion, and airway responsiveness to histamine in ovalbumin-sensitized guinea pigs (48). While CO has been shown to decrease inflammation and airway hyperresponsiveness in mice (49), recent data suggest that bilirubin may mediate the protective effects of HO-1 on airway smooth muscle cell remodeling in asthma (50).

CHRONIC OBSTRUCTIVE PULMONARY DISEASE Oxidative stress plays an important role in the pathogenesis of COPD (24). Oxidants from either cigarette smoke or inflammatory cells may directly injure the lung or indirectly damage the lung parenchyma by inactivating antiproteases that promote extracellular matrix degradation. While cigarette smoke may upregulate HO-1 expression in macrophages within alveolar spaces (51), evidence suggests that patients with COPD have reduced levels of HO-1 in alveolar macrophages isolated from BAL fluid (52). In addition, polymorphisms of the HO-1 promoter associated with reduced HO-1 expression have recently been linked with increased susceptibility to emphysema (53). This suggests a possible association between smokers with inadequate HO-1 induction and an increased risk of developing COPD. Interestingly, Shinohara and colleagues demonstrated that adenoviral overexpression of HO-1 in mice attenuated pancreatic elastase-induced inflammation, proinflammatory cytokine production, and airspace enlargement (54), further supporting a beneficial role of HO-1 in COPD. In addition, recent data suggest that polymorphisms of the HO-1 promoter are also associated with increased susceptibility to pneumonia (55), an intriguing finding as respiratory infections are the most frequent cause of COPD exacerbations.

CYSTIC FIBROSIS Inflammation and oxidative stress play a role in the progression of lung disease in patients with CF. Previous studies have demonstrated that patients with CF and bronchiectasis have elevated levels of exhaled CO (56). Furthermore, a recent study showed that HO-1 expression correlated with severity of disease in patients with CF and that overexpression of HO-1 in a CF airway epithelial cell line attenuated cellular injury and apoptosis induced by Pseudomonas (20). These findings may have implications for novel therapeutic approaches, as discussed below.

IDIOPATHIC PULMONARY FIBROSIS The pathogenesis of idiopathic pulmonary fibrosis is complex and has not yet been fully elucidated. Studies suggest that oxidative stress plays a role in the pathogenesis of IPF (57) and that HO-1 is up-regulated in alveolar macrophages of patients with interstitial lung disease (58). While a recent study suggested that pharmacologic inhibition of HO-1 abrogated bleomycin-induced pulmonary fibrosis (59), Tsuburai and coworkers demonstrated adenoviral HO-1 overexpression to be beneficial in a bleomycininduced pulmonary fibrosis model in mice (60). Similarly, both bilirubin and CO have recently been shown to ameliorate fibrosis in the bleomycin model (21, 61). While mounting evidence supports a protective role for HO-1 in pulmonary fibrosis, the mechanism underlying its beneficial effect requires further investigation.

LUNG CANCER HO-1 may play an important role in tumor growth and metastases, given its antiproliferative and antiapoptotic properties.

HO-1 Series

However, recent evidence suggests that increased levels of HO-1 may accelerate tumor angiogenesis (62) and that inhibition of HO may have antitumor activity (63). Furthermore, Kikuchi and colleagues recently reported that patients with lung adenocarcinoma had a significantly higher frequency of a specific HO-1 promoter polymorphism (L class [GT]n polymorphism, discussed below) (64), suggesting a possible association between reduced HO-1 expression and the development of lung adenocarcinoma.

BRONCHIOLITIS OBLITERANS/LUNG TRANSPLANTATION Chronic rejection in the form of bronchiolitis obliterans (BO) is the major cause of late morbidity and mortality after lung transplantation and is manifested by progressive airflow obstruction and hypoxemia. Recent data suggest that HO-1 may play an important role in acute and chronic rejection after lung transplantation. HO-1 expression is increased in alveolar macrophages of lung transplant recipients with acute cellular rejection (ACR) and BO (25, 65) and correlates with severity of rejection in a rat lung transplant model of ACR (66). Deficiency of HO-1 was detrimental in a heterotopic tracheal transplant model of BO with accelerated development of airway rejection in mice lacking HO-1 (67). While pharmacologic induction of HO-1 did not alter rejection in this model (67), Song and coworkers recently demonstrated anti-inflammatory and antiapoptotic effects of exogeneous CO administration in a rat orthotopic lung transplantation model (68). More recently, Minamoto and colleagues demonstrated a protective role for HO-1 in a tracheal transplant model of BO (69). Induction of HO-1 with cobalt protoporphyrin (CoPP) or CO administration significantly decreased luminal occlusion after transplant, while lack of HO-1 in HO-1–/– mice or zinc protoporphyrin (ZnPP)treated mice increased luminal occlusion (69). Interestingly, their results suggested that absence of HO-1 in donor graft epithelium, rather than in recipient leukocytes, was critical for driving airway occlusion after transplantation (69).

POLYMORPHISMS OF THE HO-1 PROMOTER To date, there has only been a single reported case of a patient with HO-1 deficiency who died in childhood (70). There has been increasing recognition, however, that polymorphisms of the HO-1 promoter that lead to reduced HO-1 expression may be associated with an increased risk of a variety of respiratory diseases, including emphysema, pneumonia, and lung cancer (53, 55, 64). The most extensively studied HO-1 gene variant is the dinucleotide repeat polymorphism, [GT]n, within the proximal promoter, at approximately ⫺200 base pairs (53). It is a good candidate for a functional polymorphism, since it may modulate the transcriptional activity of the gene, but its clinical significance remains unclear. The length of the dinucleotide repeat ranges from [GT]10 to [GT]40, and thus represents a continuum of alleles (53). A major obstacle in comparing studies is that genotype definitions are inconsistent. [GT]25 has often been used as a cutoff, with dinucleotide repeat lengths ⭐ 25 classified as Short (S) alleles and repeat lengths ⭓ 26 classified as Long (L) alleles. However, the S allele cutoff can vary from [GT]23 to [GT]30, and certain studies introduce a Middle (M) allele class, the definition of which is also variable. In addition, most of the analyses to date are limited to regional patient populations, with studies of pulmonary disease involving predominantly Asians and cardiovascular studies involving whites. Although the population homogeneity in these studies may increase the sensitivity of

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detecting a genetic association, the applicability of a particular association to other ethnic groups is questionable. Table 2 summarizes the association studies to date. Although the emphasis of this review is the role of HO-1 in pulmonary disease, we will briefly review genetic association studies for nonpulmonary diseases as well. In spite of confounding variables in study design, a trend has emerged over the last few years. Studies suggest that patients with the S-class [GT]n polymorphism exhibit better outcomes in cardiopulmonary disease, compared with the L-class allele. In pulmonary disease, the L-class genotype has been associated with increased susceptibility to smoking-induced emphysema, compared with the S-class genotype (71). Budhi and colleagues found a similar association in Japanese men (72), but these results could not be reproduced in a white population (53). In addition, recent reports suggest that the L-class genotype may also be associated with lung adenocarcinoma in male smokers (64) and with susceptibility to pneumonia in elderly Japanese (55). In cardiovascular disease, the S-class genotype has been associated with attenuated restenosis after angioplasty or stent implantation (53), and a decreased inflammatory response after angioplasty (53). Similarly, in another study, Gulesserian and coworkers (73) found a detrimental effect of the L-class genotype on restenosis after stent placement. The S-class genotype has also been associated with favorable outcomes in high-risk Asian patients with coronary artery disease (CAD) (53). However, these findings were not reproduced in a low-risk white population, although the S-class genotype was associated with a more favorable lipid profile and higher bilirubin levels (53). More recently, a longitudinal study of white patients with peripheral artery disease (74) revealed that S-class carriers had a reduced risk of coronary events. While these studies suggest that the S-class allele is only beneficial in high-risk patients, a more recent study of patients with ischemic cerebrovascular disease demonstrated a protective effect of the S-class allele which was limited to low-risk patients (75). In transplantation, neither the donor nor the recipient [GT]n genotype has been linked with the outcome of cardiac allografts (76), although the S-class genotype has been associated with improved renal allograft function and survival (53). The S-class genotype may also have beneficial effects in patients with abdominal aortic aneurysm (53), oral squamous cell carcinoma (77), patency of arteriovenous fistulas (78), and longevity in healthy Japanese (79). However, the S-class has also been associated with increased susceptibility to idiopathic recurrent miscarriage (53) and cerebral malaria (80). No association of the [GT]n polymorphism has been found with Kawasaki’s disease or neonatal hyperbilirubinemia (53). The underlying assumption in these studies is that beneficial outcomes associated with the S-class genotype are due to enhanced expression of the HO-1 gene. This hypothesis has not been confirmed, particularly in the cell types pertinent to the pathologies described. [GT]n dinucleotide repeats are among the most frequent simple repeats scattered throughout the human genome. In certain cases, [GT]n repeats have been shown to alter transcriptional activity of proximal promoters, possibly through the adoption of a Z-DNA conformation (81, 82), although this has yet to be demonstrated for the HO-1 promoter. Studies to elucidate the effect of the [GT]n repeat on HO-1 promoter activity are ongoing. In addition to the [GT]n polymorphism, there are reports of at least one SNP in the proximal HO-1 promoter, namely T(⫺413)A, that has been associated with disease susceptibility. The AA genotype of the T(⫺413)A polymorphism correlated with a reduced incidence of ischemic heart disease (83), despite

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TABLE 2. ASSOCIATION OF HEME OXYGENASE-1 [GT]N PROMOTER POLYMORPHISMS WITH DISEASE Sample Size Pulmonary disease Emphysema in smokers Emphysema in smokers Pneumonia in elderly Lung adenocarcinoma in male smokers Lung function decline rate in smokers Cardiovascular disease Restenosis after angioplasty Restenosis after angioplasty Inflammatory markers after angioplasty Restenosis after stenting Restenosis after stenting Coronary adverse effects in PAD CAD in the presence of risk factors CAD in Type II diabetes Cerebrovascular events in the absence of HL Abdominal aortic aneurysms CAD in whites Kawasaki disease Cardiac allograft function (Recipient) Cardiac allograft function (Donor) Cardiac allograft function (Recipient) Renal disease Renal allograft function (Donor) Renal allograft survival (Donor) Other disease entities Idiopathic recurrent miscarriage Arteriovenus fistula patency Longevity in healthy Japanese Cerebral malaria Oral squamous cell carcinoma Neonatal hyperbilirubinemia

Genotype Definition

Genotype Classes Compared S-class

L-class

Odds Ratio

% Association S-class L-class Population Age Male Reference

201 235 200

S⬍25⬍M⬍30⬍L [SS⫹SM⫹MM] [SL⫹ML⫹LL] S⬍30⬍L SS [SL⫹LL] S⬍27⬍M⬍33⬍L [SS⫹SM⫹MM] [SL⫹ML⫹LL]

Y Y Y

2.40 2.80 2.10

A A A

67 100 53 100 75 50

71 72 55

128

S⬍27⬍M⬍33⬍L [SS⫹SM⫹MM] [SL⫹ML⫹LL]

Y

3.30

A

63 100

53

594

S⬍27⬍M⬍33⬍L [SS⫹SM⫹MM] [SL⫹ML⫹LL]

N

W

49

62

53

96 210

S⬍25⬍M⬍28⬍L [SS⫹SM⫹SL] S⬍25⬍L [SS⫹SL]

[MM⫹ML⫹LL] LL

Y Y

0.20 0.37

W W

69 72

64 47

53 53

150 323 199 472 577 796

S⬍25⬍M⬍28⬍L S⬍26⬍L S⬍29⬍L S⬍25⬍L S⬍25⬍L S⬍23⬍M⬍32⬍L

[SS⫹SM⫹SL] [SS⫹SL] SS [SS⫹SL] SS [SS⫹SM⫹MM]

[MM⫹ML⫹LL] LL [SL⫹LL] LL LL [SL⫹ML⫹LL]

Y Y Y Y Y Y

0.20

W A W W A A

72 69 61 69 63 69

56 94 71 56 84 90

53 53 73 74 53 53

897 271 649 61

S⬍25⬍L S⬍25⬍L S⬍25⬍L S⬍27⬍M⬍33⬍L

0.20 0.35

W W W A

58 71 ND 24

52 73 ND 59

75 53 53 53

S⬍27⬍L S⬍27⬍L S⬍25⬍L

LL LL LL All individual genotypes LL LL LL

Y Y N N

304 253 152

SS [SS⫹SL] [SS⫹SL] All individual genotypes [SS⫹SL] [SS⫹SL] [SS⫹SL]

N N N

W W W

47 27 49

83 80 93

53 53 76

101 384

S⬍25⬍L S⬍25⬍L

[SS⫹SL] [SS⫹SL]

LL LL

Y Y

W W

48 47

56 54

53 53

291 603 512 150

S⬍27⬍L S⬍30⬍L S⬍25⬍M⬍30⬍L S⬍28⬍M⬍34⬍L

[SS⫹SL] SS [SS⫹SM⫹MM] SS

Y Y Y Y

301 149

S⬍25⬍M⬍31⬍L S allelotype S⬍27⬍M⬍33⬍L All individual genotypes

LL [SL⫹LL] [SL⫹ML⫹LL] [SM⫹SL⫹MM⫹ ML⫹LL] L allelotype All individual genotypes

Y N

5.18 3.40 0.46* 0.23 4.20

0.86† 0.50* 0.54 2.04 0.56

W A A A

32 0 60 53 n/a 51 23 ND

53 78 79 80

1.75

A A

51 100 n/a ND

77 53

3.14

Definition of abbreviations: A, Asian; CAD, coronary artery disease; HL, hyperlipidemia; ND, no data; PAD, peripheral artery disease; W, white. * Adjusted hazards ratio. † Relative serum creatine levels at 1 yr.

an increased risk of hypertension in women (84). Both studies involved large Asian populations, and the predominant haplotypes were [GT]30;(⫺413)A (39%) and [GT]23;(⫺413)T (28%). The impact of the T(⫺413)A SNP on HO-1 promoter activity remains unclear. These genetic association studies have focused on proximal promoter polymorphisms that may impact HO-1 gene expression and/or inducibility. Additional studies are necessary to establish the impact of these polymorphisms on the transcriptional activity and the inducibility of the HO-1 promoter in response to a specific stimulus in a cell type relevant to a particular lung disease.

THERAPEUTIC POTENTIALS Animal studies suggest that overexpression of HO-1 is beneficial in several lung diseases, including ALI (29, 35), pulmonary hypertension (13, 14), COPD (54), and pulmonary fibrosis (60), while inhibition of HO-1 may be protective in other disease processes such as malignancy (63). Possible approaches to modulate HO-1 expression in patients include gene therapy, pharmacologic inducers or inhibitors of HO-1, and HO-1–targeted

siRNA. Therapeutic applications of CO and bilirubin in pulmonary disease are reviewed separately (37). Intratracheal or intranasal adenoviral transfer of HO-1 is beneficial in rodent models of hyperoxia-induced lung injury (29), aerosolized LPS-induced lung injury (85), Pseudomonasinduced (86) and influenza-induced lung injury (87), elastaseinduced emphysema (54), and bleomycin-induced pulmonary fibrosis (60). Direct transpulmonary delivery has been demonstrated in neonatal mice and achieved high levels of HO-1 in type II pneumocytes, but surprisingly led to increased oxidative injury (88). Other groups have reported efficient retroviral transfer of human HO-1 to pulmonary endothelial cells in vitro (89). These studies suggest that exogenous HO-1 gene transfer may be a therapeutic approach to treat a variety of respiratory diseases; however, significant challenges regarding safe and efficient tissuespecific transfer to humans remain. The synthetic terpenoids CDDO and CDDO-imidazole are potent inducers of HO-1 that exhibit antiproliferative and anti-inflammatory properties in vitro (90), and may have future clinical applications in pulmonary medicine. Finally, therapies to reduce HO-1 expression include imidazole-dioxolane compounds that are highly specific

HO-1 Series

for inhibiting HO-1 (91) as well as siRNA (92) which may hold promise in the future.

Conclusion Animal studies have amply demonstrated that HO-1 plays a critical protective role in several different disease processes within the lung. The beneficial effects of HO-1 may one day be achieved through gene therapy, pharmacologic HO-1 inducers, or the products of HO-1 enzymatic activity, including bilirubin and CO. Therapeutic applications of bilirubin and CO, either by inhalation or CO releasing molecules (CORM) (93), will be reviewed separately in this series (37). Conflict of Interest Statement : None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript. Acknowledgments : The authors apologize to the many authors whose significant works were omitted due to space constraints. The authors are grateful to Dr. Stephen R. Walsh and Dr. Rebecca M. Baron for careful review of the manuscript.

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