The Role of Hypoxia-Inducible Factor-1 a in Response to Injury and Hypoxia* Anthony J. Baldea, MD Fred A. Luchette, MD, MSc Division of Trauma, Critical Care and Acute Care Surgery Department of Surgery Stritch School of Medicine Loyola University of Chicago Maywood, IL
t is with great interest that we read the article by Suresh et al (1) in this issue of Critical Care Medicine. This article joins the growing body of literature demonstrating that hypoxia-inducible factor (H IF)-la is a significant contributor to the cellular signaling pathways that are involved in the body’s adaptive response to hypoxia (2-4). Posttranslational modifi cations of this oxygen-sensitive transcription factor have been demonstrated to be involved in hypoxia-induced apoptosis (5) and the cell’s ability to survive in hypoxia-associated con ditions (6). Furthermore, due to the purported role of HIFl a in tumor growth and angiogenesis (7), polymorphisms in H IF -la genotypes have been proposed to be associated with an increased risk of a variety of malignancies, including lung cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, multiple myeloma, and head and neck cancer (8-11). Suresh et al (1) present novel murine research that demon strates the role of H IF -la as a potentially vital participating transcription factor in the inflammatory response following lung contusion (LC). Although other authors have explored the role of H IF -la in a variety of pulmonary perturbations, this research represents, to the authors’ best knowledge, the first article to specifically address the role of H IF -la in LC. Pre viously, Eckle et al (12) had identified H IF -la as a prominent transcriptional regulator in hypoxic conditions that affects the release of pulmonary adenosine, thus potentially further attenuating the degree of lung inflammation during acute lung injury. The increased expression of H IF -la in patients with chronic bronchitis (13) and lung ischemia-reperfusion injury (14) has also been reported by other authors. In addition, chronic hypoxic conditions have been shown to contribute to HIF-la-mediated changes in pulmonary vascular remodeling and the development of pulmonary hypertension (15). In the current study, the authors set out to determine the role of H IF -la in the pathogenesis of the acute inflammatory
I
response to pulmonary injury by studying the sequelae of blunt LC in a murine model. A nonlethal, unilateral LC was induced in H IF -la knockout mice and was compared to the control group of wild-type mice. The degree of acute inflam mation was assessed through postmortem bronchoalveolar lavage cell analysis as well as the measurement of albumin and cytokine levels. In addition, type 2 alveolar epithelial cells were specifically isolated and evaluated for proinflammatory cytokine levels. At all of the time points of analysis, the wildtype mice demonstrated increased hypoxia, a greater severity of systemic organ perfusion deficits, and an increased degree of acute inflammation. H IF -la has also been demonstrated to modulate the release of multiple mediators in this acute inflammatory process (interleukin-1(3 and nuclear factor-KB). The authors should be commended for their ongoing work studying the role of H IF -la in the inflammatory response to injury and hypoxia. As they discuss in the article, much remains unknown regarding the underlying pathophysiologic mechanisms in LC that then progress to acute respiratory dis tress syndrome. The identification of H IF -la as a key media tor in the initial inflammatory process following LC carries the potential to have both prognostic and therapeutic clinical implications. The early recognition of the injured patient with a genetic polymorphism or physiologic deviation in H IF -la activity may aid the critical care physician in identifying the subset of patients that are at increased susceptibility for the development of respiratory failure. More importantly, the identification of the key mediators in the inflammatory cas cade mediating this clinical deterioration following LC pin points a conceivable area of focus for therapeutic intervention to ameliorate this inflammatory process. The theoretical role of the therapeutic clinical manipulation of cell signaling path ways initiated by H IF -la has been described as a potential therapy in patients with malignancy (11). The authors of this article (and others) have noted in previous work that there are alterations in H IF -la activity following the administration of agents such as doxycycline and acraflavine; further work with such agents examining the clinical implications following their administration in the live animal would be needed to under stand any potentially useful applications of this manipulation of the inflammatory process.
REFERENCES *See also p. e642. Key Words: hypoxia-inducible factor-1 a; interleukin-1 (3; lung contusion; nuclear factor-KB; response to injury
1. Suresh MV, Ramakrishnan SK, Thomas B, et al: Activation of HypoxiaInducible Factor-1 a in Type 2 Alveolar Epithelial Cell Is a Major Driver of Acute Inflammation Following Lung Contusion. Crit Care Med 2014; 4 2 :e 6 4 2 -e 6 5 3
Dr. Luchette has disclosed that he provided expert testimony. Dr. Baldea has disclosed that he does not have any potential conflicts of interest.
2. Brocato J, Chervona Y, Costa M: Molecular responses to hypoxiainducible factor 1 a and beyond. Mol Pharmacol 2014; 85:651 -6 5 7
Copyright © 2014 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins
3. Tsuchida S, Arai Y, Takahashi KA, et al: HIF-1 a-induced HSP70 regu lates anabolic responses in articular chondrocytes under hypoxic con ditions. J Orthop Res 2014; 3 2 :9 7 5 -9 8 0
DOI: 10.1097/CCM.0000000000000568
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O ctober 2014 • Volume 42 • Number 10
Editorials 4. Ben Lassoued A, Beaufils N, Dales JP, et al: Hypoxia-inducible factor1a as prognostic marker. Expert Opin M ed Diagn 2013; 7 :5 3-7 0 5. Sun G, Zhou Y, Li H, et al: Over-expression of microRNA-494 upregulates hypoxia-inducible factor-1 alpha expression via PI3K/Akt pathway and protects against hypoxia-induced apoptosis. J Biom ed S ci 2013; 20:100
10. Zhou Y, Lin L, Wang Y, et al: The association between hypoxia-induc ible factor-1 a gene G 1790A polymorphism and cancer risk: A meta analysis of 28 case-control studies. Cancer C ell Int 2014; 14:37 11. Borsi E, Perrone G, Terragna C, et al: Hypoxia inducible factor-1 alpha as a therapeutic target in multiple myeloma. Oncotarget 2014; 5 :1 779-1792
6. Bagnall J, Leedale J, Taylor SE, et al: Tight control of hypoxia-inducible factor-a transient dynamics is essential for cell survival in hypoxia. J B io l Chem 2014; 2 8 9 :5 5 4 9 -5 5 6 4
12. Eckle T, Kewley EM, Brodsky KS, et al: Identification of hypoxia-induc ible factor HIF-1A as transcriptional regulator of the A2B adenosine receptor during acute lung injury. J Immunol 2014; 192:1 2 4 9 -1 256
7. Zheng X, Zhou AX, Rouhi P, et al: Hypoxia-induced and calpaindependent cleavage of filamin A regulates the hypoxic response. Proc Natl Acad S ci U S A 2014; 1 1 1 :2 5 6 0 -2 5 6 5
13. Lee SH, Lee SH, Kim CH, et al: Increased expression of vascular endothelial growth factor and hypoxia inducible factor-1 a in lung tissue of patients with chronic bronchitis. Clin Biochem 2014; 4 7 :5 5 2 -5 5 9
8. Xia T, Cheng H, Zhu Y: Knockdown of hypoxia-inducible factor-1 alpha reduces proliferation, induces apoptosis and attenuates the aggressive phenotype of retinoblastoma WERI-Rb-1 cells under hypoxic conditions. Ann Clin Lab S ci 2014; 4 4 :1 3 4 -1 4 4
14. Zhou Z, Zhu X, Chen J, et al: The interaction between Toll-like recep tor 4 signaling pathway and hypoxia-inducible factor 1a in lung isch emia-reperfusion injury. J Surg Res 2014; 1 8 8 :2 9 0 -2 9 7
9. Ye Y, Wang M, Hu S, et al: Hypoxia-inducible factor-1 a C1772T poly morphism and cancer risk: A meta-analysis including 18,334 sub jects. Cancer Invest 2014; 3 2 :1 2 6 -1 3 5
15. Ball MK, Waypa GB, Mungai PT, et al: Regulation of hypoxia-induced pulmonary hypertension by vascular smooth muscle hypoxia-inducible factor-1 a. Am J Respir Crit Care M ed 2014; 1 8 9 :3 1 4 -3 2 4
Critical Care Medicine
w w w .c c m jo u rn a l.o rg
2313
Copyright of Critical Care Medicine is the property of Lippincott Williams & Wilkins and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
t is with great interest that we read the article by Suresh et al (1) in this issue of Critical Care Medicine. This article joins the growing body of literature demonstrating that hypoxia-inducible factor (H IF)-la is a significant contributor to the cellular signaling pathways that are involved in the body’s adaptive response to hypoxia (2-4). Posttranslational modifi cations of this oxygen-sensitive transcription factor have been demonstrated to be involved in hypoxia-induced apoptosis (5) and the cell’s ability to survive in hypoxia-associated con ditions (6). Furthermore, due to the purported role of HIFl a in tumor growth and angiogenesis (7), polymorphisms in H IF -la genotypes have been proposed to be associated with an increased risk of a variety of malignancies, including lung cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, multiple myeloma, and head and neck cancer (8-11). Suresh et al (1) present novel murine research that demon strates the role of H IF -la as a potentially vital participating transcription factor in the inflammatory response following lung contusion (LC). Although other authors have explored the role of H IF -la in a variety of pulmonary perturbations, this research represents, to the authors’ best knowledge, the first article to specifically address the role of H IF -la in LC. Pre viously, Eckle et al (12) had identified H IF -la as a prominent transcriptional regulator in hypoxic conditions that affects the release of pulmonary adenosine, thus potentially further attenuating the degree of lung inflammation during acute lung injury. The increased expression of H IF -la in patients with chronic bronchitis (13) and lung ischemia-reperfusion injury (14) has also been reported by other authors. In addition, chronic hypoxic conditions have been shown to contribute to HIF-la-mediated changes in pulmonary vascular remodeling and the development of pulmonary hypertension (15). In the current study, the authors set out to determine the role of H IF -la in the pathogenesis of the acute inflammatory
I
response to pulmonary injury by studying the sequelae of blunt LC in a murine model. A nonlethal, unilateral LC was induced in H IF -la knockout mice and was compared to the control group of wild-type mice. The degree of acute inflam mation was assessed through postmortem bronchoalveolar lavage cell analysis as well as the measurement of albumin and cytokine levels. In addition, type 2 alveolar epithelial cells were specifically isolated and evaluated for proinflammatory cytokine levels. At all of the time points of analysis, the wildtype mice demonstrated increased hypoxia, a greater severity of systemic organ perfusion deficits, and an increased degree of acute inflammation. H IF -la has also been demonstrated to modulate the release of multiple mediators in this acute inflammatory process (interleukin-1(3 and nuclear factor-KB). The authors should be commended for their ongoing work studying the role of H IF -la in the inflammatory response to injury and hypoxia. As they discuss in the article, much remains unknown regarding the underlying pathophysiologic mechanisms in LC that then progress to acute respiratory dis tress syndrome. The identification of H IF -la as a key media tor in the initial inflammatory process following LC carries the potential to have both prognostic and therapeutic clinical implications. The early recognition of the injured patient with a genetic polymorphism or physiologic deviation in H IF -la activity may aid the critical care physician in identifying the subset of patients that are at increased susceptibility for the development of respiratory failure. More importantly, the identification of the key mediators in the inflammatory cas cade mediating this clinical deterioration following LC pin points a conceivable area of focus for therapeutic intervention to ameliorate this inflammatory process. The theoretical role of the therapeutic clinical manipulation of cell signaling path ways initiated by H IF -la has been described as a potential therapy in patients with malignancy (11). The authors of this article (and others) have noted in previous work that there are alterations in H IF -la activity following the administration of agents such as doxycycline and acraflavine; further work with such agents examining the clinical implications following their administration in the live animal would be needed to under stand any potentially useful applications of this manipulation of the inflammatory process.
REFERENCES *See also p. e642. Key Words: hypoxia-inducible factor-1 a; interleukin-1 (3; lung contusion; nuclear factor-KB; response to injury
1. Suresh MV, Ramakrishnan SK, Thomas B, et al: Activation of HypoxiaInducible Factor-1 a in Type 2 Alveolar Epithelial Cell Is a Major Driver of Acute Inflammation Following Lung Contusion. Crit Care Med 2014; 4 2 :e 6 4 2 -e 6 5 3
Dr. Luchette has disclosed that he provided expert testimony. Dr. Baldea has disclosed that he does not have any potential conflicts of interest.
2. Brocato J, Chervona Y, Costa M: Molecular responses to hypoxiainducible factor 1 a and beyond. Mol Pharmacol 2014; 85:651 -6 5 7
Copyright © 2014 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins
3. Tsuchida S, Arai Y, Takahashi KA, et al: HIF-1 a-induced HSP70 regu lates anabolic responses in articular chondrocytes under hypoxic con ditions. J Orthop Res 2014; 3 2 :9 7 5 -9 8 0
DOI: 10.1097/CCM.0000000000000568
2312
w w w .c c m jo u r n a l.o r g
O ctober 2014 • Volume 42 • Number 10
Editorials 4. Ben Lassoued A, Beaufils N, Dales JP, et al: Hypoxia-inducible factor1a as prognostic marker. Expert Opin M ed Diagn 2013; 7 :5 3-7 0 5. Sun G, Zhou Y, Li H, et al: Over-expression of microRNA-494 upregulates hypoxia-inducible factor-1 alpha expression via PI3K/Akt pathway and protects against hypoxia-induced apoptosis. J Biom ed S ci 2013; 20:100
10. Zhou Y, Lin L, Wang Y, et al: The association between hypoxia-induc ible factor-1 a gene G 1790A polymorphism and cancer risk: A meta analysis of 28 case-control studies. Cancer C ell Int 2014; 14:37 11. Borsi E, Perrone G, Terragna C, et al: Hypoxia inducible factor-1 alpha as a therapeutic target in multiple myeloma. Oncotarget 2014; 5 :1 779-1792
6. Bagnall J, Leedale J, Taylor SE, et al: Tight control of hypoxia-inducible factor-a transient dynamics is essential for cell survival in hypoxia. J B io l Chem 2014; 2 8 9 :5 5 4 9 -5 5 6 4
12. Eckle T, Kewley EM, Brodsky KS, et al: Identification of hypoxia-induc ible factor HIF-1A as transcriptional regulator of the A2B adenosine receptor during acute lung injury. J Immunol 2014; 192:1 2 4 9 -1 256
7. Zheng X, Zhou AX, Rouhi P, et al: Hypoxia-induced and calpaindependent cleavage of filamin A regulates the hypoxic response. Proc Natl Acad S ci U S A 2014; 1 1 1 :2 5 6 0 -2 5 6 5
13. Lee SH, Lee SH, Kim CH, et al: Increased expression of vascular endothelial growth factor and hypoxia inducible factor-1 a in lung tissue of patients with chronic bronchitis. Clin Biochem 2014; 4 7 :5 5 2 -5 5 9
8. Xia T, Cheng H, Zhu Y: Knockdown of hypoxia-inducible factor-1 alpha reduces proliferation, induces apoptosis and attenuates the aggressive phenotype of retinoblastoma WERI-Rb-1 cells under hypoxic conditions. Ann Clin Lab S ci 2014; 4 4 :1 3 4 -1 4 4
14. Zhou Z, Zhu X, Chen J, et al: The interaction between Toll-like recep tor 4 signaling pathway and hypoxia-inducible factor 1a in lung isch emia-reperfusion injury. J Surg Res 2014; 1 8 8 :2 9 0 -2 9 7
9. Ye Y, Wang M, Hu S, et al: Hypoxia-inducible factor-1 a C1772T poly morphism and cancer risk: A meta-analysis including 18,334 sub jects. Cancer Invest 2014; 3 2 :1 2 6 -1 3 5
15. Ball MK, Waypa GB, Mungai PT, et al: Regulation of hypoxia-induced pulmonary hypertension by vascular smooth muscle hypoxia-inducible factor-1 a. Am J Respir Crit Care M ed 2014; 1 8 9 :3 1 4 -3 2 4
Critical Care Medicine
w w w .c c m jo u rn a l.o rg
2313
Copyright of Critical Care Medicine is the property of Lippincott Williams & Wilkins and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
