Although not the focus of this review, it is important to underscore two important processes. The first is that such a microcirculatory alteration may create areas of hypoperfusion and hypoxia (29, 30) in parallel to the mechanisms that we will describe and that these loci of hypoxia may contribute to the inflammatory process and to the adaptive metabolic downregulation of the renal tubular cell through a process known as oxygen conformance (31). The second is the potential role of nitric oxide (NO) in the genesis of microvascular dysfunction and in the pathophysiology of AKI. Although it is known that sepsis elicits a global increment in production of NO (32), the expression of one of the most important catalyzers of its production, inducible NO synthase (iNOS), is heterogeneous (32). Therefore, it is reasonable to consider that heterogeneous expression of iNOS may result in heterogeneous regional concentrations of NO, which could potentially lead to pockets of vascular beds deprived of NO even in the setting of elevated systemic levels (33). This is important as it directly relates to the heterogeneous pattern that has been described in sepsis-induced microvascular dysfunction and furthermore may relate to possible pathophysiologic phenomena such as shunting and hypoxia (33). Nevertheless, the relationship between NO, microvascular dysfunction, and AKI may not be as straightforward, as sepsis may also cause an iNOS-dependent decrease in endothelial-derived NO synthase activity, which would also result in impaired microvascular homeostasis (34, 35). Finally, selective inhibition of iNOS not only can restore the renal microcirculatory derangements brought about by sepsis, but also is associated with decreased histological and functional manifestations of renal injury, suggesting that microcirculatory abnormalities may be in the mechanistic pathway of sepsis-induced AKI (27).
The tubular cell response to this rarefied peritubular microenvironment seems to be adaptive in origin. The bland histology and the surprising paucity of apoptosis and necrosis in septic kidneys support this notion and have led to the understanding that sepsis-induced AKI does not follow the same injury pattern as ischemia-reperfusion and hemorrhage and that it is not characterized by acute tubular necrosis (9). On the contrary, the tubular epithelial cell appears to limit processes that can otherwise activate apoptotic and necrotic signaling pathways, notably energy imbalance and DNA damage. Accordingly, we propose that the initial insult to the tubular epithelial cell is framed by inflammation and oxidative stress and that this triggers an adaptive response characterized by suppressing energy turnover, downregulating metabolism through prioritization of energy consumption (19, 41–43), and undergoing cell cycle arrest (Fig. 3) (44). We submit that this response, orchestrated by mitochondria (see below), limits further injury by maintaining energy balance and preventing further DNA damage and is central to providing the cell with an opportunity to regain function once danger has abated.
In addition, this oxidative stress response seems to be the result of an organized interaction between DAMPs and PAMPs and the tubular epithelial cell rather than a random event. Damage-associated molecular patterns and PAMPs originating from remote sites of injury or infection can gain access to the renal tubules by glomerular filtration or by proximity to the peritubular capillaries (47). Furthermore, sepsis induces renal-wide expression of otherwise constitutively expressed TLR-4 (48), and DAMPs/PAMPs are actively recognized by tubular epithelial cells through TLR-4 (22). Kalakeche et al. (22) have elegantly shown that TLR-4–dependent LPS recognition in the tubular epithelial cells occurs in the S1 segment of the proximal tubule, that assembly of LPS with TLR-4 in the tubular epithelial cell produces internalization of LPS through fluid-filled endocytosis, and that this triggers an organized oxidative outburst in epithelial cells of the adjacent tubular segments (S2 and S3) but not in the S1 segment (Fig. 2) (22). These findings have led Kalakeche et al. (22) to suggest that the S1 segment of the proximal tubule acts as a “sensor of danger” that activates a series of events resulting in oxidative stress within distal tubular segments (S2, S3) and that could potentially explain tubular dysfunction in the setting of sepsis. We further hypothesize that this oxidative outburst is the trigger for the adaptive response of the tubular epithelial cell, which is characterized by reprioritizing energy expenditure, downregulating metabolism, and undergoing cell cycle arrest (Fig. 3).
Apoptosis is the principal mechanism of programmed cell death in multicellular organisms (49). It can be triggered by a myriad of stimuli including DNA damage, energy failure, growth factor deprivation, and endoplasmic reticulum stress (49), all of which also occur as a consequence of sepsis. Yet, tubular cell apoptosis is largely absent in patients with sepsis-induced AKI. It is likely that the scarcity of apoptosis is mainly orchestrated by mitochondria, as these organelles are central in the process of triggering the programmed cell death machinery (50). Importantly, mitochondria influence three key processes that could potentially lead to apoptosis: (a) energy homeostasis and prioritization of energy consumption, (b) maintenance of cellular organelle function through quality control processes (general autophagy and mitophagy), and (c) cell cycle and DNA replication. We submit that these processes not only are fundamental aspects of the adaptive response of the tubular epithelial cell, but also explain, at least in part, the sepsis-induced AKI phenotype.
Autophagy (and the specialized process of mitochondrial removal called mitophagy) is an evolutionarily conserved, quality control mechanism, by which eukaryotic cells remove and digest dysfunctional organelles from the cytoplasm (55, 56). During sepsis, TLR-4–mediated inflammation (57), oxidative stress (58, 59), and alterations in the electron transport chain that “uncouple” respiration from ATP production and depolarize the mitochondrial membrane are potent triggers of mitophagy (56). This early mitochondrial uncoupling characterized by an increment in O2 consumption (VO2) is not to be confused with the adaptive response it triggers, which is framed by the activation of mitophagy, and is characterized by a decrement in VO2 and conservation of energy.
On the other hand, stimulation of autophagy has been shown to be effective at protecting organ function. Gunst et al. (61) showed in critically ill rabbits that treatment with rapamycin (a potent inductor of mitophagy) was associated with protection of renal function. Similarly, Hsiao et al. (60) showed that preincubation of NRK-52E cells (proximal tubule epithelial cell line) with rapamycin prevented tumor necrosis factor α–induced cell death, whereas inhibition of autophagy exaggerated it. Furthermore, they demonstrated in CLP-induced septic rats that a decline in autophagy was associated with increased BUN and creatinine and a decline in proximal tubular sodium transport (60).
As a protective response, mitophagy offers several advantages, namely, removal of dysfunctional mitochondria, with subsequent decrement in ROS/RNS production and energy conservation, as “nonessential” energy consumption from uncoupled respiration is reduced, and lipids and proteins are recycled for ulterior use as a source of energy. Importantly, these benefits may limit oxidative stress damage and intercept proapoptotic signals at the mitochondrial level impeding triggering of apoptosis (56). Finally, there is also evidence that cross-talk between autophagy and apoptosis does occur, as they both share common factors, interconnections, and regulatory steps (62–64).
It is unknown, however, what mitophagy-induced maintenance of renal function really means. The adaptive response, framed by metabolic downregulation and prioritization of energy consumption, would most likely decrease tubular and renal function and not promote it, just as hibernation promotes functio laesa. Indeed, increased or preserved renal function in the setting of stress may result harmful in the long run. Yet, animal and human data associate acute stimulation of autophagy with preserved renal function, and its faulty activation or decline with worse outcome. It is possible that the interplay of autophagy and tubular cell function varies with time and that persistence of the initial protective response may ultimately be deleterious in the subacute or chronic phases.
One of the most important advantages of understanding the mechanistic underpinnings of a disease process is the possibility it offers to find novel and, more importantly, effective therapeutic interventions. In no other disease process, affecting the critically ill, is this more true than in sepsis. For decades, therapeutic efforts have failed to significantly reduce mortality. The unifying theory presented herein provides a possible roadmap to unraveling the pathophysiology of sepsis-induced AKI, a known driver of mortality in this population. Furthermore, if proven, new avenues to attack this disease process, at different stages, may be opened. Indeed, stage-specific manipulation of inflammation, microvascular dysfunction, and of cellular energy regulation may provide a new way to prevent and/or treat sepsis-induced AKI and possible other sepsis-induced organ failures. The recognition of the derangement in microcirculatory flow, for example, has triggered the investigation of therapeutic strategies to understand how to maintain or reestablish microvascular autoregulation that would have never been conceived should this not have been recognized. For example, the use of vasodilators in the setting of sepsis is currently under investigation including use of systemic vasoactive medications (71–75), modulation of NO production, exogenous NO administration, and protection of the endothelial cell in the context of inflammatory activation (30, 33, 35, 76, 77). In the same way, animal data have suggested that stimulation of evolutionarily conserved, intrinsic cellular mechanisms that regulate energy utilization and quality control processes may result in organ protection in the setting of sepsis-induced AKI (78). Indeed, the conservation and promotion of autophagy have been shown to be associated with better prognosis in septic animals and humans (55, 61). In summary, we believe that this unifying theory may shed light on possible future targets for intervention, destined to protecting the microvasculature and the endothelium, balancing energy utilization and modulating inflammation.
We emphasize that this “unifying theory” is not a universal theory, and thus, many other potentially important processes have not been considered. Nevertheless, the data hereby presented may provide new avenues of investigation that will hopefully lead to unraveling the mechanisms by which sepsis induces AKI and, better yet, mechanistic patterns that govern global organ dysfunction in this setting that may facilitate the development of more and better targeted future therapies.
The authors thank Dr Michael R. Pinsky, Brian Zuckerbraun, and Alonso Gomez for their valuable input in the conception of this theory and review of this article.
1. Uchino S, Kellum JA, Bellomo R, et al.: Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA
294 (7): 813–818, 2005.
2. Murugan R, Karajala-Subramanyam V, Lee M, et al.: Acute kidney injury
in non-severe pneumonia is associated with an increased immune response and lower survival. Kidney Int
77 (6): 527–535, 2010.
3. Langenberg C, Wan L, Egi M, May CN, Bellomo R: Renal blood flow in experimental septic acute renal failure. Kidney Int
69 (11): 1996–2002, 2006.
4. Langenberg C, Bellomo R, May C, Wan L, Egi M, Morgera S: Renal blood flow in sepsis
. Crit Care
9 (4): R363–R374, 2005.
5. Chua HR, Glassford N, Bellomo R: Acute kidney injury
after cardiac arrest. Resuscitation
83 (6): 721–727, 2012.
6. Zager RA: Partial aortic ligation: a hypoperfusion model of ischemic acute renal failure and a comparison with renal artery occlusion. J Lab Clin Med
110 (4): 396–405, 1987.
7. Cerchiari EL, Safar P, Klein E, Diven W: Visceral, hematologic and bacteriologic changes and neurologic outcome after cardiac arrest in dogs. The visceral post-resuscitation syndrome. Resuscitation
25 (2): 119–136, 1993.
8. Mariano F, Cantaluppi V, Stella M, et al.: Circulating plasma factors induce tubular and glomerular alterations in septic burns patients. Crit Care
12 (2): R42, 2008.
9. Rosen S, Heyman SN: Difficulties in understanding human “acute tubular necrosis”: limited data and flawed animal models. Kidney Int
60 (4): 1220–1224, 2001.
10. Brenner M, Schaer GL, Mallory DL, Suffredini AF, Parrillo JE: Detection of renal blood flow abnormalities in septic and critically ill patients using a newly designed indwelling thermodilution renal vein catheter. Chest
98 (1): 170–179, 1990.
11. Di Giantomasso D, Bellomo R, May CN: The haemodynamic and metabolic effects of epinephrine in experimental hyperdynamic septic shock. Intensive Care Med
31 (3): 454–462, 2005.
12. Di Giantomasso D, May CN, Bellomo R: Vital organ blood flow during hyperdynamic sepsis
124 (3): 1053–1059, 2003.
13. Di Giantomasso D, May CN, Bellomo R: Norepinephrine and vital organ blood flow during experimental hyperdynamic sepsis
. Intensive Care Med
29 (10): 1774–1781, 2003.
14. Ravikant T, Lucas CE: Renal blood flow distribution in septic hyperdynamic pigs. J Surg Res
22 (3): 294–298, 1977.
15. Wan L, Bellomo R, May CN: The effect of normal saline resuscitation on vital organ blood flow in septic sheep. Intensive Care Med
32 (8): 1238–1242, 2006.
16. Wang Z, Holthoff JH, Seely KA, et al.: Development of oxidative stress in the peritubular capillary microenvironment mediates sepsis
-induced renal microcirculatory failure and acute kidney injury
. Am J Pathol
180 (2): 505–516, 2012.
17. Seely KA, Holthoff JH, Burns ST, et al.: Hemodynamic changes in the kidney in a pediatric rat model of sepsis
-induced acute kidney injury
. Am J Physiol Renal Physiol
301 (1): F209–F217, 2011.
18. De Backer D, Creteur J, Preiser JC, Dubois MJ, Vincent JL: Microvascular blood flow is altered in patients with sepsis
. Am J Respir Crit Care Med
166 (1): 98–104, 2002.
19. Singer M, De Santis V, Vitale D, Jeffcoate W: Multiorgan failure is an adaptive, endocrine-mediated, metabolic response to overwhelming systemic inflammation
364 (9433): 545–548, 2004.
20. Hotchkiss RS, Karl IE: The pathophysiology and treatment of sepsis
. N Engl J Med
348 (2): 138–150, 2003.
21. Fry DE: Sepsis
, systemic inflammatory response, and multiple organ dysfunction: the mystery continues. Am Surg
78 (1): 1–8, 2012.
22. Kalakeche R, Hato T, Rhodes G, et al.: Endotoxin uptake by S1 proximal tubular segment causes oxidative stress in the downstream S2 segment. J Am Soc Nephrol
22 (8): 1505–1516, 2011.
23. Wu L, Gokden N, Mayeux PR: Evidence for the role of reactive nitrogen species in polymicrobial sepsis
-induced renal peritubular capillary dysfunction and tubular injury. J Am Soc Nephrol
18 (6): 1807–1815, 2007.
24. 24. De Backer D, Creteur J, Preiser J-C, Dubois M-J, Vincent J-L: Microvascular blood flow is altered in patients with sepsis
. 166: 98–104, 2002.
25. De Backer D, Donadello K, Taccone FS, Ospina-Tascon G, Salgado D, Vincent JL: Microcirculatory alterations: potential mechanisms and implications for therapy. Ann Intensive Care
1 (1): 27, 2011.
26. Verdant CL, De Backer D, Bruhn A, et al.: Evaluation of sublingual and gut mucosal microcirculation
: a quantitative analysis. Crit Care Med
37 (11): 2875–2881, 2009.
27. Tiwari MM, Brock RW, Megyesi JK, Kaushal GP, Mayeux PR: Disruption of renal peritubular blood flow in lipopolysaccharide-induced renal failure: role of nitric oxide and caspases. Am J Physiol Renal Physiol
289 (6): F1324–F1332, 2005.
28. Holthoff JH, Wang Z, Seely KA, Gokden N, Mayeux PR: Resveratrol improves renal microcirculation
, protects the tubular epithelium, and prolongs survival in a mouse model of sepsis
-induced acute kidney injury
. Kidney Int
81 (4): 370–378, 2012.
29. Dyson A, Bezemer R, Legrand M, Balestra G, Singer M, Ince C: Microvascular and interstitial oxygen tension in the renal cortex and medulla studied in a 4-h rat model of LPS-induced endotoxemia. Shock
36 (1): 83–89, 2011.
30. Almac E, Siegemund M, Demirci C, Ince C: Microcirculatory recruitment maneuvers correct tissue CO2
abnormalities in sepsis
. Minerva Anestesiol
72 (6): 507–519, 2006.
31. Schumacker PT, Chandel N, Agusti AG: Oxygen conformance of cellular respiration in hepatocytes. Am J Physiol
265 (4 Pt 1): L395–L402, 1993.
32. Cunha FQ, Assreuy J, Moss DW, et al.: Differential induction of nitric oxide synthase in various organs of the mouse during endotoxaemia: role of TNF-alpha and IL-1-beta. Immunology
81 (2): 211–215, 1994.
33. Trzeciak S, Cinel I, Phillip Dellinger R, et al.: Resuscitating the microcirculation
: the central role of nitric oxide, emerging concepts for novel therapies, and challenges for clinical trials. Acad Emerg Med
15 (5): 399–413, 2008.
34. Chauhan SD, Seggara G, Vo PA, Macallister RJ, Hobbs AJ, Ahluwalia A: Protection against lipopolysaccharide-induced endothelial dysfunction in resistance and conduit vasculature of iNOS knockout mice. FASEB J
17 (6): 773–775, 2003.
35. Heemskerk S, Masereeuw R, Russel FG, Pickkers P: Selective iNOS inhibition for the treatment of sepsis
-induced acute kidney injury
. Nat Rev Nephrol
5 (11): 629–640, 2009.
36. Goddard CM, Allard MF, Hogg JC, Herbertson MJ, Walley KR: Prolonged leukocyte transit time in coronary microcirculation
of endotoxemic pigs. Am J Physiol
269 (4 Pt 2): H1389–H1397, 1995.
37. Wu L, Tiwari MM, Messer KJ, et al.: Peritubular capillary dysfunction and renal tubular epithelial cell stress following lipopolysaccharide administration in mice. Am J Physiol Renal Physiol
292 (1): F261–F268, 2007.
38. Wu X, Guo R, Wang Y, Cunningham PN: The role of ICAM-1 in endotoxin-induced acute renal failure. Am J Physiol Renal Physiol
293 (4): F1262–F1271, 2007.
39. Bezemer R, Legrand M, Klijn E, et al.: Real-time assessment of renal cortical microvascular perfusion heterogeneities using near-infrared laser speckle imaging. Optics Expr
18 (14): 15054–15061, 2010.
40. Legrand M, Bezemer R, Kandil A, Demirci C, Payen D, Ince C: The role of renal hypoperfusion in development of renal microcirculatory dysfunction in endotoxemic rats. Intensive Care Med
37 (9): 1534–1542, 2011.
41. Brealey D, Brand M, Hargreaves I, et al.: Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet
360 (9328): 219–223, 2002.
42. Brealey D, Karyampudi S, Jacques TS, et al.: Mitochondrial dysfunction in a long-term rodent model of sepsis
and organ failure. Am J Physiol Regul Integr Comp Physiol
286 (3): R491–R497, 2004.
43. Brealey D, Singer M: Mitochondrial dysfunction in sepsis
. Curr Infect Dis Rep
5 (5): 365–371, 2003.
44. Yang QH, Liu DW, Long Y, Liu HZ, Chai WZ, Wang XT: Acute renal failure during sepsis
: potential role of cell cycle
regulation. J Infect
58 (6): 459–464, 2009.
45. Gupta A, Rhodes GJ, Berg DT, Gerlitz B, Molitoris BA, Grinnell BW: Activated protein C ameliorates LPS-induced acute kidney injury
and downregulates renal INOS and angiotensin 2. Am J Physiol Renal Physiol
293 (1): F245–F254, 2007.
46. Good DW, George T, Watts BA 3rd: Lipopolysaccharide directly alters renal tubule transport through distinct TLR4-dependent pathways in basolateral and apical membranes. Am J Physiol Renal Physiol
297 (4): F866–F874, 2009.
47. El-Achkar TM, Hosein M, Dagher PC: Pathways of renal injury in systemic gram-negative sepsis
. Eur J Clin Invest
38 (Suppl 2): 39–44, 2008.
48. El-Achkar TM, Huang X, Plotkin Z, Sandoval RM, Rhodes GJ, Dagher PC: Sepsis
induces changes in the expression and distribution of Toll-like receptor 4 in the rat kidney. Am J Physiol Renal Physiol
290 (5): F1034–F1043, 2006.
49. Ferraro E, Cecconi F: Autophagic and apoptotic response to stress signals in mammalian cells. Arch Biochem Biophys
462 (2): 210–219, 2007.
50. Green DR: The end and after: how dying cells impact the living organism. Immunity
35 (4): 441–444, 2011.
51. Atkinson D: Cellular Energy Metabolism and Its Regulation
. Atkinson D, ed. New York: Academic Press, pp. 218, 1977.
52. Buttgereit F, Brand MD: A hierarchy of ATP-consuming processes in mammalian cells. Biochem J
312 (Pt 1): 163–167, 1995.
53. Buck LT, Hochachka PW, Schon A, Gnaiger E: Microcalorimetric measurement of reversible metabolic suppression induced by anoxia in isolated hepatocytes. Am J Physiol
265 (5 Pt 2): R1014–R1019, 1993.
54. Carre JE, Singer M: Cellular energetic metabolism in sepsis
: the need for a systems approach. Biochim Biophys Acta
1777 (7–8): 763–771, 2008.
55. Vanhorebeek I, Gunst J, Derde S, et al.: Mitochondrial fusion, fission, and biogenesis in prolonged critically ill patients. J Clin Endocrinol Metab
97 (1): E59–E64, 2012.
56. Green DR, Galluzzi L, Kroemer G: Mitochondria
and the autophagy-inflammation
-cell death axis in organismal aging. Science
333 (6046): 1109–1112, 2011.
57. Waltz P, Carchman EH, Young AC, et al.: Lipopolysaccharide induces autophagic signaling in macrophages via a TLR4, heme oxygenase-1 dependent pathway. Autophagy
7 (3): 315–320, 2011.
58. Frank M, Duvezin-Caubet S, Koob S, et al.: Mitophagy is triggered by mild oxidative stress in a mitochondrial fission dependent manner. Biochim Biophys Acta
1823 (12): 2297–2310, 2012.
59. Wang Y, Nartiss Y, Steipe B, McQuibban GA, Kim PK: ROS-induced mitochondrial depolarization initiates PARK2/PARKIN-dependent mitochondrial degradation by autophagy. Autophagy
8 (10): 1462–1476, 2012.
60. Hsiao HW, Tsai KL, Wang LF, et al.: The decline of autophagy contributes to proximal tubular dysfunction during sepsis
37 (3): 289–296, 2012.
61. Gunst J, Derese I, Aertgeerts A, et al.: Insufficient autophagy contributes to mitochondrial dysfunction, organ failure, and adverse outcome in an animal model of critical illness. Crit Care Med
41 (1): 182–194, 2013.
62. Mizushima N, Levine B, Cuervo AM, Klionsky DJ: Autophagy fights disease through cellular self-digestion. Nature
451 (7182): 1069–1075, 2008.
63. Levine B, Yuan J: Autophagy in cell death: an innocent convict? J Clin Invest
115 (10): 2679–2688, 2005.
64. Ciechomska IA, Goemans CG, Tolkovsky AM: Molecular links between autophagy and apoptosis. Methods Mol Biol
445: 175–193, 2008.
65. Finkel T, Hwang PM: The Krebs cycle meets the cell cycle
and the G1-S transition. Proc Natl Acad Sci U S A
106 (29): 11825–11826, 2009.
66. Mitra K, Wunder C, Roysam B, Lin G, Lippincott-Schwartz J: A hyperfused mitochondrial state achieved at G1-S regulates cyclin E buildup and entry into S phase. Proc Natl Acad Sci U S A
106 (29): 11960–11965, 2009.
67. Schieke SM, McCoy JP Jr, Finkel T: Coordination of mitochondrial bioenergetics with G1 phase cell cycle
progression. Cell Cycle
7 (12): 1782–1787, 2008.
68. Mandal S, Guptan P, Owusu-Ansah E, Banerjee U: Mitochondrial regulation of cell cycle
progression during development as revealed by the tenured mutation in Drosophila
. Dev Cell
9 (6): 843–854, 2005.
69. Kashani K, Al-Khafaji A, Ardiles T, et al.: Discovery and validation of cell cycle
arrest biomarkers in human acute kidney injury
. Crit Care
17 (1): R25, 2013.
70. Singh P, Okusa MD: The role of tubuloglomerular feedback in the pathogenesis of acute kidney injury
. Contrib Nephrol
174: 12–21, 2011.
71. Boerma EC, Koopmans M, Konijn A, et al.: Effects of nitroglycerin on sublingual microcirculatory blood flow in patients with severe sepsis
/septic shock after a strict resuscitation protocol: a double-blind randomized placebo controlled trial. Crit Care Med
38 (1): 93–100, 2010.
72. de Backer D, Creteur J, Dubois MJ, et al.: The effects of dobutamine on microcirculatory alterations in patients with septic shock are independent of its systemic effects. Crit Care Med
34 (2): 403–408, 2006.
73. de Backer D, Verdant C, Chierego M, Koch M, Gullo A, Vincent JL: Effects of drotrecogin alfa activated on microcirculatory alterations in patients with severe sepsis
. Crit Care Med
34 (7): 1918–1924, 2006.
74. Pleiner J, Mittermayer F, Schaller G, MacAllister RJ, Wolzt M: High doses of vitamin C reverse Escherichia coli
endotoxin-induced hyporeactivity to acetylcholine in the human forearm. Circulation
106 (12): 1460–1464, 2002.
75. Tyml K, Li F, Wilson JX: Delayed ascorbate bolus protects against maldistribution of microvascular blood flow in septic rat skeletal muscle. Crit Care Med
33 (8): 1823–1828, 2005.
76. de Caterina R, Libby P, Peng HB, et al.: Nitric oxide decreases cytokine-induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. J Clin Invest
96 (1): 60–68, 1995.
77. Goldfarb RD, Cinel I: Inhaled nitric oxide therapy for sepsis
: more than just lung. Crit Care Med
35 (1): 290–292, 2007.
78. Howell GM GH, Collage RD, Loughran P, Escobar D, Zhang X, Billiar TR, Zuckerbraun BS, Rosengart MR: Augmenting autophagy to treat acute kidney injury
during endotoxemia in mice. PLoS One
8 (7): e69520, 2013.
79. Bonventre JV, Yang L: Cellular pathophysiology of ischemic acute kidney injury
. J Clin Invest
121 (11): 4210–4221, 2011.