help button home button
AJRCCM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Published ahead of print on January 7, 2004, doi:10.1164/rccm.200303-372OC
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Online Supplement
Right arrow All Versions of this Article:
200303-372OCv1
169/6/749    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Deng, J.
Right arrow Articles by Star, R. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Deng, J.
Right arrow Articles by Star, R. A.
American Journal of Respiratory and Critical Care Medicine Vol 169. pp. 749-756, (2004)
© 2004 American Thoracic Society

Original Article

{alpha}-Melanocyte–stimulating Hormone Inhibits Lung Injury after Renal Ischemia/Reperfusion

Jiangping Deng, Xuzhen Hu, Peter S. T. Yuen and Robert A. Star

Renal Diagnostics and Therapeutics Unit, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland

Correspondence and requests for reprints should be addressed to Robert A. Star, M.D., Renal Diagnostics and Therapeutics Unit, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 10, Room 3N108, 10 Center Drive, Bethesda, MD 20892-1268. E-mail: Robert_Star{at}nih.gov


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Combined acute renal and pulmonary failure has a very high mortality. In animals, lung injury develops after shock or visceral or renal ischemia. {alpha}-Melanocyte–stimulating hormone ({alpha}-MSH) is an antiinflammatory cytokine, which inhibits inflammatory, apoptotic, and cytotoxic pathways implicated in acute renal injury. We sought to determine if {alpha}-MSH inhibits acute lung injury after renal ischemia and to determine the early mechanisms of {alpha}-MSH action. Mice were subjected to renal ischemia treated with vehicle or {alpha}-MSH. At early time points, we measured organ histology, leukocyte accumulation, myeloperoxidase activity, activation of nuclear factor-{kappa}B, p38 mitogen-activated protein kinase, c-Jun, and activator protein-1 pathways, in addition to messenger RNA for intracellular adhesion molecule-1 and tumor necrosis factor-{alpha}. Renal ischemia rapidly activated kidney and lung nuclear factor-{kappa}B, p38 mitogen-activated protein kinase, c-Jun, and activator protein-1 pathways, and distant lung injury. {alpha}-MSH administration immediately before reperfusion significantly decreased kidney and lung injury and prevented activation of kidney and lung transcription factors and stress response genes, and lung intracellular adhesion molecule-1 and tumor necrosis factor-{alpha} at early time points after renal ischemia/reperfusion. We conclude that distant lung injury occurs rapidly after renal ischemia. {alpha}-MSH protects against both kidney and lung damage after renal ischemia, in part, by inhibiting activation of transcription factors and stress genes early after renal injury.

Key Words: inflammation • nuclear factor-{kappa}B • p38 • leukocytes • intracellular adhesion molecule-1 • tumor necrosis factor-{alpha}

The mortality of combined acute renal failure and acute respiratory failure is extremely high, and may approach 80% (1). Severe trauma, burns, hemorrhage, sepsis, shock, or severe local tissue injury can trigger a systemic inflammatory response that leads to multiple organ failure and death (2). There are epidemiologic and pathogenic links between renal and pulmonary injury. Much of the increased risk attributable to acute renal failure after cardiac surgery comes from nonrenal complications such as respiratory failure (3). Severe tissue injury, as occurs after prolonged lower torso ischemia or complicated abdominal aortic aneurysm surgery, can induce acute respiratory distress syndrome (ARDS) (4–6). In animal models, secondary (or distant) lung injury can be triggered by severe local ischemia to the liver (7), GI tract (8), hind limb (9), and kidney (10), or after chemical pancreatitis (11). For example, renal ischemia/reperfusion injury increases pulmonary vascular permeability, interstitial edema, alveolar hemorrhage, and red blood cell sludging (10). Because the lung has the largest microcapillary network in the body, it responds to circulating proinflammatory signals with activation of lung macrophages, secretion of proinflammatory cytokines, recruitment of neutrophils and macrophages, and resultant lung injury (12).

There are many similarities among the local injury pathways activated after acute pulmonary and renal injury and secondary lung injury. Renal ischemia/reperfusion causes apoptosis and necrosis of proximal straight tubules and inflammatory infiltration of leukocytes (13). Early in the reperfusion period there is activation of stress-activated kinases (for example, p38 mitogen-activated protein kinase [MAPK]) and transcription factors nuclear factor-{kappa}B (NF-{kappa}B) and activator protein-1 (AP-1) and induction of proinflammatory cytokines (tumor necrosis factor-{alpha} [TNF-{alpha}]) and adhesion molecules (intracellular adhesion molecule-1 [ICAM-1]) (14–17). Selective inhibition of TNF-{alpha} (16) or ICAM-1 (18, 19) decreases acute renal injury. Similar proinflammatory, NF-{kappa}B, p38, and AP-1 pathways are activated after acute lung injury (reviewed in [20–22]) and (23), and inhibition of NF-{kappa}B (7) or p38 (24, 25) attenuates distant lung injury. However, no agent has been shown to inhibit both the local injury and the secondary lung injury. For example, the p38 inhibitor CNI-1493 partially attenuated the distant lung injury but had no effect on the underlying renal ischemia/reperfusion injury (10).

{alpha}-Melanocyte–stimulating hormone ({alpha}-MSH) is an antiinflammatory cytokine that inhibits acute, chronic, and systemic inflammation. MSH inhibits renal injury from ischemia/reperfusion, cisplatin administration, or after transplantation from a marginal donor, but not after mercury administration (26–28). The mechanism of action of {alpha}-MSH is broad, including inhibition of inflammatory, cytotoxic, and apoptotic pathways that are activated after renal ischemia (26, 27, 29, 30). We previously found that {alpha}-MSH inhibits TNF-{alpha} and ICAM-1 activation at 4 hours after reperfusion (26, 27). However, the early molecular mechanism of action of {alpha}-MSH is not well understood. In the ischemia/reperfusion and other disease models, {alpha}-MSH inhibits the production of many cytokines, chemokines, and inducible nitric oxide synthase, suggesting that {alpha}-MSH acts at a step or steps common to early inflammation pathways. Recent studies have shown that {alpha}-MSH suppresses NF-{kappa}B stimulation in brain inflammation (31) and in cultured cells exposed to LPS (31–33). {alpha}-MSH also inhibits p38 MAPK in B16 melanoma cells (34), and AP-1 DNA–binding activity in dermal fibroblasts (32, 35, 36), but not in macrophages (32, 35).

Therefore, we determined if {alpha}-MSH could decrease lung injury caused by renal ischemia and reperfusion. We also investigated the effects of {alpha}-MSH on early activation of transcription factors and stress gene activation in both the kidney and lung. Some the results of these studies have been previously reported in the form of an abstract (37).


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
(Detailed METHODS are described in the online supplement.)

Chemicals
{alpha}-MSH was purchased from Phoenix Pharmaceuticals (Mountain View, CA). All antibodies were purchased from Cellular Signaling Technology (Beverly, MA).

Animal Model
Male C57BL/6J mice were subjected to 40 minutes bilateral renal ischemia or sham surgery as described (26, 27). We adhered to National Institutes of Health criteria for the care and use of laboratory animals in research. Twenty-five micrograms of {alpha}-MSH or vehicle (0.3 ml normal saline) was given intravenously immediately before the clamps were removed (26, 29). When reperfusion time was 24 hours, the animals were given additional {alpha}-MSH or vehicle at 8 and 16 hours postischemia. Blood was collected for measurement of serum creatinine (Astra 8 autoanalyzer; Beckman, Fullerton, CA).

Lung Wet/Dry Ratio
Parenchymal lung samples were blotted, weighed, and baked to obtain dry weights. The ratio of wet to dry weight was used as an indicator of pulmonary edema.

Organ Histology and Esterase Staining
Formalin-fixed and paraffin-embedded specimens were stained with hematoxylin and eosin (4 µm sections) or naphthol AS-D chloroacetate esterase (3-µm sections). Renal injury was measured as described (26, 27). Lung injury was defined as increased interstitial cellularity within the pulmonary parenchyma and/or extension of cellular infiltrates into the alveolar space. Lung injury was evaluated semiquantitatively on the basis of the percentage of parenchymal area involved (1+: < 10%; 2+: 10–30%; 3+: > 30% involvement) in five 25x fields per section. Most infiltrating cells were segmented neutrophils with some additional mononuclear (macrophage) infiltrates (38). Because the esterase stain identifies both neutrophils and macrophages (39), we use the term leukocyte below. Leukocyte infiltration was measured by counting five 25x fields per section.

Tissue Myeloperoxidase Determination
Tissue myeloperoxidase (MPO) activity was assayed to monitor the degree of inflammation (26, 38, 40). MPO activity was assessed spectrophotometrically using tetramethylbenzidine and expressed as the change in absorbance per milligram of wet weight per minute.

Reverse Transcriptase–Polymerase Chain Reaction Assay
Total RNA was isolated using TRIzol (Invitrogen, Carlsbad, CA), and reverse transcriptase–polymerase chain reaction was performed as described (27).

Cytoplasmic and Nuclear Protein Isolation
Cytoplasmic and nuclear proteins were isolated as described (41). Protein concentration was determined by protein assay (Pierce Chemical, Rockford, IL).

Electrophoretic Mobility Shift Assay
NF-{kappa}B and AP-1 binding activities were determined by electrophoretic mobility shift assay (41). Competition experiments were performed by preincubating nuclear proteins with 100-fold excess unlabeled consensus oligonucleotide.

Western Blot Detection of p65, p38, and Phosphorylated I{kappa}B{alpha}
Samples (10 µg protein) were analyzed by Western blotting with primary antibody (1:1,000) and horseradish peroxidase–conjugated secondary antibody.

p38 MAPK Activity
Samples were immunoprecipitated with immobilized phospho-p38 MAPK (Thr180/tyr182) antibody, incubated with adenosine triphosphate (ATP) and activating transcription factor-2 fusion protein (a p38 MAPK substrate), and detected by Western blotting using a phospho-activating transcription factor-2 (Thr71) antibody.

Phosphorylation of c-Jun
Cytoplasmic samples were incubated with immobilized c-Jun (1–89) fusion protein beads and ATP, and the phosphorylated product was measured by Western blotting using a phospho-c-Jun (Ser63) antibody.

Statistical Analysis
All data are presented as mean ± SEM. Different treatments were compared using t tests or analysis of variance techniques followed by Dunnett's test. The null hypothesis was rejected when p values were less than 0.05.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Effect of {alpha}-MSH on Lung Injury after Renal Ischemia/Reperfusion
We found histologic evidence of lung injury 4 hours after renal ischemia that consisted of swollen interstitial spaces, increased interstitial cellularity, and inflammation in the alveolar space (Figure 1B) compared with sham-operated animals (Figure 1A). Treatment with {alpha}-MSH before release of the clamp decreased the histologic changes (Figure 1C). These changes were evaluated by semiqualitative histology of lung injury and lung wet/dry ratio. {alpha}-MSH significantly decreased lung injury (Figure 2A) at 4 hours after renal ischemia. Because the thickened alveolar walls suggested the presence of interstitial edema, we measured the ratio of wet to dry lung weight, a marker of lung edema (Figure 2B). Renal ischemia/reperfusion significantly increased lung edema at 4 and 8 hours after clamping. {alpha}-MSH significantly decreased lung edema at both time points.



View larger version (88K):
[in this window]
[in a new window]
  		Figure 1. Typical lung histology after renal ischemia. Animals were studied 4 hours after sham surgery (A and D) or after 40 minutes ischemia and vehicle (B and E) or 25 µg {alpha}-melanocyte–stimulating hormone ({alpha}-MSH) treatment (C and F). Sections were stained with hematoxylin and eosin (H&E) (A–C) or leukocyte esterase (D–F). Inset: higher magnification of E; arrowheads depict leukocyte esterase–positive cells.

 


View larger version (19K):
[in this window]
[in a new window]
  		Figure 2. Effect of {alpha}-MSH on lung injury, leukocyte accumulation, and edema after renal ischemia. Animals were subjected to 40 minutes ischemia, given 25 µg {alpha}-MSH or vehicle, and 4 hours reperfusion. (A) Lung injury and leukocyte accumulation were measured as described in METHODS (n = 3–4 animals per group). (B) Lung wet/dry ratio measured at 4 or 8 hours after renal ischemia or sham surgery (n = 5–6 animals per group). *p Values less than 0.05 versus sham; +p values less than 0.05 versus vehicle.

 
Effect of {alpha}-MSH on Renal Injury after Renal Ischemia/Reperfusion
Serum creatinine was increased significantly at 4, 8, and 24 hours after renal ischemia/reperfusion as compared with the sham-operated animals. At each time point, animals receiving {alpha}-MSH had significantly lower creatinine levels compared with the vehicle-treated group (Figure 3A) and also less necrosis and fewer casts assessed by quantitative histology at the 4-hour time point (Figure 3B).



View larger version (20K):
[in this window]
[in a new window]
  		Figure 3. Effect of renal ischemia on renal function and renal injury. (A) Animals were subjected to sham or 40 minutes ischemia surgery, given 25 µg {alpha}-MSH or vehicle, and reperfused for 4, 8, or 24 hours. Sham animals were subjected to the same surgical procedure (without clamping of the renal vessels) and then studied 8 hours later. Animals in the 24-hour group received additional doses of {alpha}-MSH at 8 and 16 hours (n = 6–8 per group). (B) Animals were subjected to 40 minutes ischemia, treated with vehicle or 25 µg {alpha}-MSH, and killed after 4 hours reperfusion. Kidney necrosis, casts, congestion, and leukocyte accumulation were measured as described in METHODS (n = 3–4 animals per group). *p Values less than 0.05 versus sham; +p values less than 0.05 versus vehicle.

 
Effect of {alpha}-MSH on Leukocyte Accumulation
Previous studies have shown that renal ischemia causes leukocyte infiltration into the kidney and lung (10, 12, 13) and that {alpha}-MSH inhibits local leukocyte accumulation after acute inflammation and renal ischemia (42). Chloroacetate esterase staining demonstrated increased leukocyte accumulation in the lung at 4 hours after renal ischemia/reperfusion (Figure 1E) compared with sham-operated animals (Figure 1D). Treatment with {alpha}-MSH before release of the clamp decreased leukocyte infiltration (Figure 1F). These changes were evaluated by counting esterase-positive cells in lung (Figure 2A) and kidney (Figure 3B). There were increased numbers of leukocytes infiltrating into the kidney and lung at very early times after renal ischemia/reperfusion injury, and the accumulation was inhibited by {alpha}-MSH. To confirm this result, we measured kidney and lung MPO activity (Figure 4) . Renal ischemia significantly increased kidney and lung MPO activity at 4 and 8 hours after ischemia. {alpha}-MSH significantly decreased MPO activity at both time points in both tissues.



View larger version (17K):
[in this window]
[in a new window]
  		Figure 4. Effect of {alpha}-MSH on kidney and lung myeloperoxidase activity induced by renal ischemia. Myeloperoxidase activity was measured from sham control mice, and mice subjected to 40 minutes of renal ischemia and reperfusion for 4 or 8 hours in the presence and absence of {alpha}-MSH. The sham animals were studied 4 hours after surgery (n = 6–11 per group). *p Values less than 0.05 versus sham; +p values less than 0.05 versus vehicle.

 
Effect of {alpha}-MSH on TNF-{alpha} and ICAM-1
Renal ischemia increases renal TNF-{alpha} and ICAM-1, and inhibition of either pathway inhibits renal injury (16, 19, 26, 43, 44). Therefore, we determined the effects of renal ischemia and {alpha}-MSH treatment on lung TNF-{alpha} and ICAM-1 messenger RNA. We found that renal ischemia upregulated lung TNF-{alpha} and ICAM-1 messenger RNA measured 4 hours after reperfusion (Figure 5) . This upregulation was inhibited in {alpha}-MSH–treated animals, similar to the effect of {alpha}-MSH in hepatic and renal injury models (26, 45).



View larger version (35K):
[in this window]
[in a new window]
  		Figure 5. Effect of {alpha}-MSH on messenger RNA (mRNA) abundance of lung tumor necrosis factor-{alpha} (TNF-{alpha}) and intracellular adhesion molecule-1 (ICAM-1) after renal ischemia. Animals were studied 4 hours after sham surgery, or subjected to 40 minutes ischemia, given vehicle or 25 µg {alpha}-MSH intravenously, then killed after 4 hours reperfusion. Lung total RNA was extracted and reverse transcriptase–polymerase chain reaction (RT-PCR) performed as described in METHODS. The size (bp) of each band is indicated on the left.

 
Early Events after Injury and Protection by {alpha}-MSH
Studies of acute organ injury have shown that signaling pathways involving NF-{kappa}B, p38 MAPK, c-Jun, and AP-1 are activated early in the injured organ, and inhibition of these pathways decreases local (14, 15, 17, 22–25, 38, 46–49) or distant lung (7, 11, 50) injury. We found that renal ischemia caused phosphorylation of cytosolic I{kappa}B{alpha} in both kidney and lung within 15–30 minutes after reperfusion (Figure 6) . Administration of {alpha}-MSH just before clamp release inhibited I{kappa}B{alpha} phosphorylation in both kidney and lung. Phosphorylation of I{kappa}B{alpha} causes its own destruction, which allows NF-{kappa}B dimers containing p65 to translocate to the nucleus. As an expected consequence of I{kappa}B{alpha} phosphorylation, p65 appearance in the nucleus occurred rapidly in both kidney and lung and was inhibited in both organs in {alpha}-MSH–treated mice. The effect of renal ischemia and {alpha}-MSH on NF-{kappa}B DNA–binding activity in kidney and lung was measured by electromobility gel shift analysis (Figure 7) . NF-{kappa}B binding activity was increased rapidly in both kidney and lung at the end of the ischemic period. {alpha}-MSH treatment inhibited NF-{kappa}B binding activity in both kidney and lung.



View larger version (63K):
[in this window]
[in a new window]
  		Figure 6. Effect of {alpha}-MSH on kidney and lung phosphorylated I{kappa}B{alpha} and nuclear p65 after renal ischemia. Phosphorylation of cytoplasmic I{kappa}B{alpha} and appearance of p65 in nucleus, which are required for nuclear factor-{kappa}B (NF-{kappa}B) activation, were measured at the indicated times after 40 minutes of renal ischemia or 60 minutes after sham surgery (S). Animals killed 60 minutes after ischemia received either 25 µg {alpha}-MSH or vehicle.

 


View larger version (67K):
[in this window]
[in a new window]
  		Figure 7. Effect of {alpha}-MSH on kidney and lung NF-{kappa}B binding after renal ischemia. Nuclear NF-{kappa}B activation was measured by electrophoretic mobility gel shift assay at indicated times after 40 minutes of bilateral renal ischemia or 60 minutes after sham surgery (S). A sample obtained 60 minutes after ischemia was examined after incubation with excess cold consensus oligonucleotide (cold) or after incubation with p65 antibody (supershift assay). Arrows indicate the supershifted bands corresponding to the oligonucleotide/p65/antibody complex. Bottom panel: Animals killed after 60 minutes received either 25 µg {alpha}-MSH or vehicle.

 
Renal ischemia/reperfusion also caused a rapid phosphorylation of kidney and lung p38, without changes in total p38 (Figure 8) . The phosphorylation of p38 was inhibited by treatment of the animals with {alpha}-MSH (Figure 8). To demonstrate the activity of phosphorylated p38, we measured phospho-p38 MAPK activity. Renal ischemia rapidly increased renal phospho-p38 MAPK activity in both organs, and the activation was decreased by {alpha}-MSH (Figure 8).



View larger version (65K):
[in this window]
[in a new window]
  		Figure 8. Effect of {alpha}-MSH on cytoplasmic total p38, phosphorylated p38, and p38 mitogen-activated protein kinase (MAPK) activity after renal ischemia. Total p38, p38 phosphorylation, and p38 MAPK activity were measured 15–240 minutes after 40 minutes of renal ischemia. In some studies, animals were treated with {alpha}-MSH or vehicle. The kidneys were removed and the cytoplasmic proteins subjected to Western blotting with antibodies to p38 or phosphorylated p38. MAPK activity was measured by immunoprecipitating phosphorylated p38 MAPK, incubating with activating transcription factor-2 (ATF-2) fusion protein, and the phosphorylation of ATF-2 was measured by Western blotting with an antibody to phospho-ATF-2.

 
Renal ischemia/reperfusion also increased the ability of pulmonary and renal homogenates to phosphorylate c-Jun (Figure 9) , which was inhibited by treating the mice with {alpha}-MSH. Because activated c-Jun binds to AP-1 binding sites (51), we evaluated AP-1 binding activity by electromobility gel shift assay. We found that renal ischemia increased AP-1 binding activity in both organs and that this effect was inhibited in {alpha}-MSH–treated animals (Figure 9).



View larger version (53K):
[in this window]
[in a new window]
  		Figure 9. Effect of {alpha}-MSH on phosphorylation of c-Jun and AP-1 binding activity after renal ischemia. Experimental design as given in Figure 7. Top panel: Phosphorylation of c-Jun/glutathione-S-transferase (GST) fusion protein by cytoplasmic proteins was measured by Western blotting at indicated times after 40 minutes renal ischemia (see METHODS). Middle panel: animals were treated with 25 µg {alpha}-MSH or vehicle and kidney or lung isolated at indicated times. Bottom panel: AP-1 DNA–binding activity was measured by an electrophoretic mobility shift assay (see METHODS). Animals received either {alpha}-MSH or vehicle.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
We found that renal ischemia rapidly causes distant lung injury and that both renal and distant lung injury are inhibited by {alpha}-MSH. The findings expand what is known about the early molecular mechanisms of the distant lung injury after renal ischemia and the mechanisms of action of {alpha}-MSH. The role of inflammation in acute lung injury caused by local or distant injury is well documented (7, 9, 12, 52–54). Kramer and coworkers previously demonstrated that renal ischemia/reperfusion causes lung injury manifested by interstitial edema, alveolar hemorrhage, red cell sludging, and increased vascular permeability at 24 hours but not 1 hour after reperfusion (10). In the present studies, we found that the injury can be easily detected as early as 4 hours after renal ischemia. The injury was confirmed by quantitative histology and lung edema. The very rapid onset of pulmonary injury also occurs after hepatic and hind-limb ischemia (7, 9). We found that inflammatory cells infiltrate into the lung rapidly after renal ischemia, as measured by counting leukocytes and MPO activity. Because of the early and intense inflammation, we tested the effects of {alpha}-MSH. We found that {alpha}-MSH has a dramatic effect on lung injury, assessed by histology, quantitative histology, and lung weight. {alpha}-MSH inhibited leukocyte infiltration into the lung at 4 and 8 hours after renal ischemia, similar to its effects in the kidney. The effect of {alpha}-MSH is more striking at 8 hours than at 4 hours, perhaps because it can inhibit a number of early stress/inflammatory responses, any or all of which could contribute to the ability of {alpha}-MSH to decrease the progression of injury. We then studied factors that have been implicated in leukocyte infiltration in inflammation such as TNF-{alpha} and ICAM-1 because inhibition of either TNF-{alpha} or ICAM-1 reduces both local organ and distant lung inflammation and injury (11, 16, 19, 43, 55). In the present studies, we found that renal ischemia/reperfusion increased pulmonary TNF-{alpha} and ICAM-1 messenger RNA 4 hours after reperfusion and that these events were inhibited by {alpha}-MSH. {alpha}-MSH caused a similar inhibition of TNF-{alpha} and ICAM-1 after renal ischemia or cisplatin administration (26, 27). TNF-{alpha} is important in distant organ injury because antibodies to TNF-{alpha} reduce lung injury after hepatic ischemia (55), and agents that decrease distant lung injury also decrease pulmonary TNF-{alpha} (7, 11, 25, 50). This evidence suggests the importance of inflammation, and TNF-{alpha} in particular, in distant lung injury induced by ischemia or damage to extrapulmonary organs (7, 11).

Some of the effects of {alpha}-MSH are likely to be mediated via direct effects on leukocytes. Neutrophils and macrophages express {alpha}-MSH receptors (56–59). {alpha}-MSH inhibits neutrophil migration in vitro and nitric oxide production from cultured macrophages (56, 58). However, {alpha}-MSH inhibits renal ischemia/reperfusion injury even in the absence of leukocyte infiltration (29), suggesting that {alpha}-MSH may also act via leukocyte-independent pathways.

The antiinflammatory effects of {alpha}-MSH are reminiscent of its effects in intradermal, air-pouch, and solid organ models of acute inflammation (45), as {alpha}-MSH decreased both local renal injury and distant pulmonary injury after renal ischemia. Previous studies have shown that distant lung injury can be partially attenuated by a p38 inhibitor given 1 to 2 hours before chemical pancreatitis (11) or renal ischemia (10), IL-10 given immediately before lung ischemia (7), or antibodies to C-X-C chemokines given immediately after hind-limb ischemia (9). The p38 inhibitor partially attenuated the lung injury but not the renal injury (10). Furthermore, the p38 inhibitor was given 1 to 2 hours before ischemia (10, 11). In contrast, {alpha}-MSH administration just before reperfusion had a greater protective effect on the pulmonary injury and also inhibited the renal injury. Although the p38 inhibitor and {alpha}-MSH treatments were not directly compared, the combined data suggest that {alpha}-MSH may act locally and distantly through common mechanisms, with p38-dependent and p38-independent components.

Pathways involving NF-{kappa}B, stress-regulated protein kinases (p38 and c-Jun), and AP-1 signaling contribute to tissue damage after acute renal and pulmonary injury. For example, acute renal injury increases renal NF-{kappa}B binding activity (17), p38 MAPK (14, 15) and c-Jun (14, 15, 48, 49), and AP-1 binding activity (49) after kidney ischemia. Lung NF-{kappa}B (7, 20, 21, 38), p38 (24, 25), c-Jun (60), and AP-1 (23) are increased after acute lung injury. Whereas inhibition of NF-{kappa}B (7, 38) or p38 (11, 50, 61) attenuates distant lung injury activation caused by lung transplantation, pancreatitis, hepatic ischemia or hemorrhage and LPS, the early events that cause lung injury after renal ischemia were not known. We found that renal ischemia increased renal and lung phosphorylation of cytoplasmic I{kappa}B{alpha}, p65 translocation into the nucleus, and increased NF-{kappa}B binding activity that involved p65. We also demonstrated that renal ischemia increased p38 MAPK activity, increased the ability of cell homogenates to phosphorylate c-Jun, and increased AP-1 binding rapidly in kidney and lung after renal ischemia. Further evidence for a role of these pathways in renal and pulmonary injury was supplied by studies examining the effects of {alpha}-MSH on these pathways. {alpha}-MSH administration at the time of clamp release inhibited both renal and lung I{kappa}B{alpha} phosphorylation, p65 appearance in the nucleus, and NF-{kappa}B binding activity, as has been noted previously in cultured cells (31–33, 36) and in vivo brain and footpad inflammation models (31, 62, 63). {alpha}-MSH administration also inhibited renal ischemia/reperfusion–induced activation of p38 MAPK, c-Jun, and AP-1 pathways in both kidney and lung. Previous studies have shown that {alpha}-MSH inhibition of p38 MAPK in B16 melanoma cells is responsible for the melanogenic and antiproliferative effects of {alpha}-MSH (34), whereas {alpha}-MSH inhibits IL-1–stimulated AP-1 DNA–binding activity in dermal fibroblasts (35); however, this effect is not widespread because {alpha}-MSH did not inhibit AP-1 activity in macrophages (32). Taken together, our findings suggest rapid activation of the I{kappa}B{alpha}/NF-{kappa}B, p38, and AP-1 pathways in kidney and the distant lung after renal ischemia and their inhibition by {alpha}-MSH.

Distant ischemic pretreatment, which inhibits c-Jun N-terminal kinase and p38 activation, prevents subsequent renal ischemia/reperfusion injury (14). Unfortunately, this intervention is not a clinically viable alternative. The ability of {alpha}-MSH to inhibit all of these pathways might explain why {alpha}-MSH inhibits both kidney and lung injury in this model, a property not shared by p38 inhibition (10). Previous drug intervention studies have focused on inhibition of single pathways (see for example [7, 25, 50]). One limitation of this approach is that these signaling pathways can interact in a target cell once they are activated by an external signal. For example, p38 can activate NF-{kappa}B (64) and also phosphorylate activating transcription factor-1 which dimerizes with phosphorylated c-Jun to form AP-1 (51). Inhibition of p38 and NF-{kappa}B decreases expression of TNF-{alpha} and ICAM-1 (reviewed in [21, 22]). Another possible mediator, poly(adenosine diphosphate-ribose) polymerase-1, which can interact with both NF-{kappa}B and AP-1, and can regulate the MAPK pathway, appears to be important in lung inflammation (65). However, neither is the effect of {alpha}-MSH on poly(ADP) polymerase-1 known nor is it known how these inflammatory pathways directly lead to edema and other endpoints in inflammation. Because of its broad mechanism of action, {alpha}-MSH may not be useful to dissect out specific pathways or distinguish between early and late stages of inflammation.

Some potential targets for the later stages of pulmonary edema have been identified, such as water (aquaporin-5), sodium channels, or the sodium pump (Na/K–ATPase) (66), as well as voltage-dependent potassium channels (67), and these targets could also be affected by {alpha}-MSH. With a number of potential interacting and/or redundant pathways and downstream targets, future studies will be needed to sort out which of these pathways are essential for inflammation.

This leaves a major question of how target cells in the lung detect signals from the kidney. High levels of uremic toxins that accumulate for 48 hours after bilateral nephrectomy can cause lung damage (66). However, the lung injury in our ischemia/reperfusion model occurs within a few hours, before uremic toxins could accumulate. TNF-{alpha} had been considered a likely candidate for this distress signal; however, hepatic or hind-limb ischemia without reperfusion activates lung NF-{kappa}B or chemokine synthesis (7, 9) even before serum TNF-{alpha} is increased (7, 9). A growing body of evidence suggests that NF-{kappa}B activation precedes and perhaps causes TNF-{alpha} secretion after myocardial ischemia and renal ischemia (17, 68). Our data support this view that TNF-{alpha} is unlikely to mediate distant lung injury, and the mediator(s) involved remain elusive. Pulmonary NF-{kappa}B binding and p38 MAPK activity dramatically increase even before the start of renal reperfusion. The ability of {alpha}-MSH to inhibit pulmonary NF-{kappa}B and p38 at the earliest time points suggests that {alpha}-MSH interferes with this kidney–lung signaling pathway after the signal reaches the lung; however, we cannot eliminate the possibility that {alpha}-MSH is acting directly on the kidney to intercept the signal. We speculate that the signal from the kidney could be a circulating factor (such as a cytokine other than TNF-{alpha} or an activated coagulation factor), a neuronal response, or an accumulation of a nonuremic toxin that is normally cleared rapidly by the kidney. Conversely, a passive mechanism may be invoked where a constant signal, perhaps antiinflammatory, is produced by the kidneys, which is then interrupted during renal ischemia; this model could explain how pulmonary NF-{kappa}B, p38 MAPK, and phospho-c-Jun could be upregulated 0 minutes after renal reperfusion. Recently, Raap and coworkers (69) demonstrated that {alpha}-MSH inhibits inflammation in response to aerosolized allergen, which establishes a direct action of {alpha}-MSH on the lung as a possible protective mechanism from renal ischemia/reperfusion.

Combined acute renal and pulmonary failure has an extremely high morbidity and mortality (1). Severe tissue injury from burns, trauma, or prolonged lower torso ischemia or complicated abdominal aortic aneurysm surgery can induce ARDS (4–6). Our current armamentarium is limited to replacing lost organ function with controlled ventilation and dialysis, preventing barotrauma, and optimizing cardiovascular function with proper volume resuscitation and inotropic support. Drug treatment lags far behind. Recently, activated protein C was shown to improve mortality in sepsis (70). Additional strategies to prevent or treat multiorgan failure would be extremely helpful. No drugs are known to reduce both pulmonary and renal injury. We found that {alpha}-MSH given just before reperfusion inhibits both acute renal and pulmonary injury after renal ischemia. We demonstrated that {alpha}-MSH inhibits leukocyte infiltration and prevents induction of I{kappa}B{alpha}/NF-{kappa}B, p38, c-Jun, and AP-1 pathways in both organs. The ability to inhibit injury in both organs, the extent of protection afforded, and the broad mechanism of action distinguishes {alpha}-MSH from other agents that protect against ischemia/reperfusion injury. This suggests that {alpha}-MSH may have important therapeutic effects in patients.


   Acknowledgments
 
The authors thank Dr. Anthony Suffredini and Marc Braunstein for their helpful comments on a previous version of this manuscript.


   FOOTNOTES
 
Supported by the National Institute of Diabetes and Digestive and Kidney Diseases.

The current affiliation for J.D. is the Burn, Shock, and Trauma Institute, Loyola University, Chicago Medical Center, Maywood, Illinois.

This article has an online data supplement, which is accessible from this issue's table of contents online at www.atsjournals.org

Conflict of Interest Statement: J.D. has no declared conflict of interest; X.H. has no declared conflict of interest; P.S.T.Y. has no declared conflict of interest; R.A.S. has no declared conflict of interest.

Received in original form March 13, 2003; accepted in final form December 30, 2003


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Chertow GM, Christiansen CL, Cleary PD, Munro C, Lazarus JM. Prognostic stratification in critically ill patients with acute renal failure requiring dialysis. Arch Intern Med 1995;155:1505–1511.[Abstract/Free Full Text]
  2. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992;20:864–874.
  3. Chertow GM, Levy EM, Hammermeister KE, Grover F, Daley J. Independent association between acute renal failure and mortality following cardiac surgery. Am J Med 1998;104:343–348.[CrossRef][Medline]
  4. Stallone RJ, Lim RC Jr, Blaisdell FW. Pathogenesis of the pulmonary changes following ischemia of the lower extremities. Ann Thorac Surg 1969;7:539–549.[Medline]
  5. Tilney NL, Bailey GL, Morgan AP. Sequential system failure after rupture of abdominal aortic aneurysms: an unsolved problem in postoperative care. Ann Surg 1973;178:117–122.[Medline]
  6. Klausner JM, Paterson IS, Mannick JA, Valeri R, Shepro D, Hechtman HB. Reperfusion pulmonary edema. JAMA 1989;261:1030–1035.[Abstract/Free Full Text]
  7. Yoshidome H, Kato A, Edwards MJ, Lentsch AB. Interleukin-10 inhibits pulmonary NF-kappaB activation and lung injury induced by hepatic ischemia-reperfusion. Am J Physiol Lung Cell Mol Physiol 1999;277:L919–L923.[Abstract/Free Full Text]
  8. Xiao F, Eppihimer MJ, Young JA, Nguyen K, Carden DL. Lung neutrophil retention and injury after intestinal ischemia/reperfusion. Microcirculation 1997;4:359–367.[Medline]
  9. Bless NM, Warner RL, Padgaonkar VA, Lentsch AB, Czermak BJ, Schmal H, Friedl HP, Ward PA. Roles for C-X-C chemokines and C5a in lung injury after hindlimb ischemia-reperfusion. Am J Physiol 1999;276:L57–L63.
  10. Kramer AA, Postler G, Salhab KF, Mendez C, Carey LC, Rabb H. Renal ischemia reperfusion leads to macrophage-mediated increase in pulmonary vascular permeability. Kidney Int 1999;55:2362–2367.[CrossRef][Medline]
  11. Yang J, Murphy C, Denham W, Botchkina G, Tracey KJ, Norman J. Evidence of a central role for p38 map kinase induction of tumor necrosis factor alpha in pancreatitis-associated pulmonary injury. Surgery 1999;126:216–222.[Medline]
  12. Rabb H, Chamoun F, Hotchkiss J. Molecular mechanisms underlying combined kidney-lung dysfunction during acute renal failure. Contrib Nephrol 2001;132:41–52.
  13. Sheridan AM, Bonventre JV. Cell biology and molecular mechanisms of injury in ischemic acute renal failure. Curr Opin Nephrol Hypertens 2000;9:427–434.[CrossRef][Medline]
  14. Park KM, Chen A, Bonventre JV. Prevention of kidney ischemia/reperfusion-induced functional injury, JNK, p38, and MAP kinase kinase activation by remote ischemic pretreatment. J Biol Chem 2001;276:11870–118706.[Abstract/Free Full Text]
  15. Yin T, Sandhu G, Wolfgang CD, Burrier A, Webb RL, Rigel DF, Hai T, Whelan J. Tissue-specific pattern of stress kinase activation in ischemic/reperfused heart and kidney. J Biol Chem 1997;272:19943–19950.[Abstract/Free Full Text]
  16. Donnahoo KK, Meng XZ, Ayala A, Cain MP, Harken AH, Meldrum DR. Early kidney TNF-{alpha} expression mediates neutrophil infiltration and injury after renal ischemia-reperfusion. Am J Physiol Regul Integr Comp Physiol 1999;277:R922–R929.[Abstract/Free Full Text]
  17. Donnahoo KK, Meldrum DR, Shenkar R, Chung CS, Abraham E, Harken AH. Early renal ischemia, with or without reperfusion, activates NFkappaB and increases TNF-alpha bioactivity in the kidney. J Urol 2000;163:1328–1332.[CrossRef][Medline]
  18. Kelly KJ, Williams WW Jr, Colvin RB, Meehan SM, Springer TA, Gutierrez-Ramos J-C, Bonventre JV. Intercellular adhesion molecule-1-deficient mice are protected against ischemic renal injury. J Clin Invest 1996;97:1056–1063.[Medline]
  19. Kelly KJ, Williams WW Jr, Colvin RB, Bonventre JV. Antibody to intercellular adhesion molecule 1 protects the kidney against ischemic injury. Proc Natl Acad Sci USA 1994;91:812–816.[Abstract/Free Full Text]
  20. Lentsch AB, Ward PA. Regulation of experimental lung inflammation. Respir Physiol 2001;128:17–22.[CrossRef][Medline]
  21. Fan J, Ye RD, Malik AB. Transcriptional mechanisms of acute lung injury. Am J Physiol Lung Cell Mol Physiol 2001;281:L1037–L1050.[Abstract/Free Full Text]
  22. Obata T, Brown GE, Yaffe MB. MAP kinase pathways activated by stress: the p38 MAPK pathway. Crit Care Med 2000;28(4 Suppl):N67–N77.
  23. Armstead VE, Opentanova IL, Minchenko AG, Lefer AM. Tissue factor expression in vital organs during murine traumatic shock: role of transcription factors AP-1 and NF-kappaB. Anesthesiology 1999;91:1844–1852.[CrossRef][Medline]
  24. Kawashima Y, Takeyoshi I, Otani Y, Koibuchi Y, Yoshinari D, Koyama T, Kobayashi M, Matsumoto K, Morishita Y. FR167653 attenuates ischemia and reperfusion injury of the rat lung with suppressing p38 mitogen-activated protein kinase. J Heart Lung Transplant 2001;20:568–574.[CrossRef][Medline]
  25. Otani Y, Takeyoshi I, Koibuchi Y, Matsumoto K, Muramoto M, Morishita Y. The effect of FR167653 on pulmonary ischemia-reperfusion injury in rats. J Heart Lung Transplant 2000;19:377–383.[CrossRef][Medline]
  26. Chiao H, Kohda Y, McLeroy P, Craig L, Housini I, Star RA. {alpha}-Melanocyte-stimulating hormone protects against renal injury after ischemia in mice and rats. J Clin Invest 1997;99:1165–1172.[Medline]
  27. Deng J, Kohda Y, Chiao H, Wang Y, Hu X, Hewitt SM, Miyaji T, MeLeroy P, Nibhanupudy B, Li S, et al. Interleukin-10 inhibits ischemic and cisplatin-induced acute renal injury. Kidney Int 2001;60:2118–2128.[CrossRef][Medline]
  28. Miyaji T, Hu X, Star RA. Alpha-melanocyte-simulating hormone and interleukin-10 do not protect the kidney against mercuric chloride-induced injury. Am J Physiol Renal Physiol 2002;282:F795–F801.[Abstract/Free Full Text]
  29. Chiao H, Kohda Y, McLeroy P, Craig L, Linas S, Star RA. {alpha}-melanocyte-stimulating hormone inhibits renal injury in the absence of neutrophils. Kidney Int 1998;54:765–774.[CrossRef][Medline]
  30. Jo SK, Yun SY, Chang KH, Cha DR, Cho WY, Kim HK, Won NH. Alpha-MSH decreases apoptosis in ischaemic acute renal failure in rats: possible mechanism of this beneficial effect. Nephrol Dial Transplant 2001;16:1583–1591.[Abstract/Free Full Text]
  31. Ichiyama T, Zhao H, Catania A, Furukawa S, Lipton JM. {alpha}-Melanocyte-stimulating hormone inhibits NF-kappaB activation and IkappaB{alpha} degradation in human glioma cells and in experimental brain inflammation. Exp Neurol 1999;157:359–365.[CrossRef][Medline]
  32. Manna SK, Aggarwal BB. {alpha}-Melanocyte-stimulating hormone inhibits the nuclear transcription factor NF-kappaB activation induced by various inflammatory agents. J Immunol 1998;161:2873–2880.[Abstract/Free Full Text]
  33. Mandrika I, Muceniece R, Wikberg JE. Effects of melanocortin peptides on lipopolysaccharide/interferon-gamma-induced NF-kappaB DNA binding and nitric oxide production in macrophage-like RAW 264.7 cells: evidence for dual mechanisms of action. Biochem Pharmacol 2001;61:613–621.[CrossRef][Medline]
  34. Smalley K, Eisen T. The involvement of p38 mitogen-activated protein kinase in the alpha-melanocyte stimulating hormone (alpha-MSH)-induced melanogenic and anti-proliferative effects in B16 murine melanoma cells. FEBS Lett 2000;476:198–202.[CrossRef][Medline]
  35. Böhm M, Schulte U, Kalden H, Luger TA. Alpha-melanocyte-stimulating hormone modulates activation of NF-kappaB and AP-1 and secretion of interleukin-8 in human dermal fibroblasts. Ann N Y Acad Sci 1999;885:277–286.[CrossRef][Medline]
  36. Gupta AK, Diaz RA, Higham S, Kone BC. Alpha-MSH inhibits induction of C/EBPbeta-DNA binding activity and NOS2 gene transcription in macrophages. Kidney Int 2000;57:2239–2248.[CrossRef][Medline]
  37. Deng J, Hu X, Yuen PST, Star RA. Early mechanisms of action of {alpha}-MSH in ischemic kidney and lung injury [abstract]. J Am Soc Nephrol 2002;13:325A.
  38. Ross SD, Kron IL, Gangemi JJ, Shockey KS, Stoler M, Kern JA, Tribble CG, Laubach VE. Attenuation of lung reperfusion injury after transplantation using an inhibitor of nuclear factor-kappaB. Am J Physiol Lung Cell Mol Physiol 2000;279:L528–L536.[Abstract/Free Full Text]
  39. Ysebaert DK, De Greef KE, Vercauteren SR, Ghielli M, Verpooten GA, Eyskens EJ, De Broe ME. Identification and kinetics of leukocytes after severe ischaemia/reperfusion renal injury. Nephrol Dial Transplant 2000;15:1562–1574.[Abstract/Free Full Text]
  40. Laight DW, Lad N, Woodward B, Waterfall JF. Assessment of myeloperoxidase activity in renal tissue after ischeaemia/reperfusion. Eur J Pharmacol 1994;292:81–88.[Medline]
  41. Li C, Browder W, Kao RL. Early activation of transcription factor NF-kappaB during ischemia in perfused rat heart. Am J Physiol 1999;276:H543–H552.
  42. Kohda Y, Chiao H, Star RA. Alpha-melanocyte-stimulating hormone and acute renal failure. Curr Opin Nephrol Hypertens 1998;7:413–417.[Medline]
  43. Daemen MARC, Van de Ven MWCM, Heineman E, Buurman WA. Involvement of endogenous interleukin-10 and tumor necrosis factor-{alpha} in renal ischemia-reperfusion injury. Transplantation 1999;67:792–800.[CrossRef][Medline]
  44. Kelly KJ, Meehan SM, Colvin RB, Williams WW, Bonventre JV. Protection from toxicant-mediated renal injury in the rat with anti-CD54 antibody. Kidney Int 1999;56:922–931.[CrossRef][Medline]
  45. Chiao H, Foster S, Thomas R, Lipton J, Star RA. {alpha}-Melanocyte-stimulating hormone reduces endotoxin-induced liver inflammation. J Clin Invest 1996;97:2038–2044.[Medline]
  46. Bonventre JV. Kidney ischemic preconditioning. Curr Opin Nephrol Hypertens 2002;11:43–48.[CrossRef][Medline]
  47. Safirstein RL. Cell cycle events during renal injury. Ren Fail 1999;21:427–431.[Medline]
  48. Pombo CM, Bonventre JV, Avruch J, Woodgett JR, Kyriakis JM, Force T. The stress-activated protein kinases are major c-Jun amino-terminal kinases activated by ischemia and reperfusion. J Biol Chem 1994;269:26546–26551.[Abstract/Free Full Text]
  49. Morooka H, Bonventre JV, Pombo CM, Kyriakis JM, Force T. Ischemia and reperfusion enhance ATF-2 and c-Jun binding to cAMP response elements and to an AP-1 binding site from the c-jun promoter. J Biol Chem 1995;270:30084–30092.[Abstract/Free Full Text]
  50. Denham W, Yang J, Wang H, Botchkina G, Tracey KJ, Norman J. Inhibition of p38 mitogen activate kinase attenuates the severity of pancreatitis-induced adult respiratory distress syndrome. Crit Care Med 2000;28:2567–2572.[CrossRef][Medline]
  51. Karin M, Liu Z, Zandi E. AP-1 function and regulation. Curr Opin Cell Biol 1997;9:240–246.[CrossRef][Medline]
  52. Seekamp A, Mulligan MS, Till GO, Ward PA. Requirements for neutrophil products and L-arginine in ischemia-reperfusion injury. Am J Pathol 1993;142:1217–1226.[Abstract]
  53. Vedder NB, Fouty BW, Winn RK, Harlan JM, Rice CL. Role of neutrophils in generalized reperfusion injury associated with resuscitation from shock. Surgery 1989;106:509–516.[Medline]
  54. Fantini GA, Conte MS. Pulmonary failure following lower torso ischemia: clinical evidence for a remote effect of reperfusion injury. Am Surg 1995;61:316–319.[Medline]
  55. Colletti LM, Remick DG, Burtch GD, Kunkel SL, Strieter RM, Campbell DA Jr. Role of tumor necrosis factor-alpha in the pathophysiologic alterations after hepatic ischemia/reperfusion injury in the rat. J Clin Invest 1990;85:1936–1943.
  56. Catania A, Rajora N, Capsoni F, Minonzio F, Star RA, Lipton JL. The neuropeptide {alpha}-MSH has specific receptors on neutrophils and reduces chemotaxis in vivo. Peptides 1996;17:675–679.[CrossRef][Medline]
  57. Rajora N, Ceriani G, Catania A, Star RA, Murphy MT, Lipton JM. {alpha}-MSH production, receptors, and influence on neopterin, in a human monocyte/macrophage cell line. J Leukoc Biol 1996;59:248–253.[Abstract]
  58. Star RA, Rajora N, Huang J, Chavez R, Catania A, Lipton JM. Evidence of autocrine modulation of macrophage nitric oxide synthase by {alpha}-melanocyte-stimulating hormone. Proc Natl Acad Sci USA 1995;92:8016–8020.[Abstract/Free Full Text]
  59. Bhardwaj R, Becher E, Mahnke K, Hartmeyer M, Schwarz T, Scholzen T, Luger TA. Evidence for the differential expression of the functional alpha- melanocyte-stimulating hormone receptor MC-1 on human monocytes. J Immunol 1997;158:3378–3384.[Abstract]
  60. Wijeweera JB, Gandolfi AJ, Parrish A, Lantz RC. Sodium arsenite enhances AP-1 and NFkappaB DNA binding and induces stress protein expression in precision-cut rat lung slices. Toxicol Sci 2001;61:283–294.[Abstract/Free Full Text]
  61. Arcaroli J, Yum HK, Kupfner J, Park JS, Yang KY, Abraham E. Role of p38 MAP kinase in the development of acute lung injury. Clin Immunol 2001;101:211–219.[CrossRef][Medline]
  62. Ichiyama T, Sakai T, Catania A, Barsh GS, Furukawa S, Lipton JM. Systemically administered {alpha}-melanocyte-stimulating peptides inhibit NF-kappaB activation in experimental brain inflammation. Bra Res 1999;836:31–37.
  63. Ichiyama T, Sakai T, Catania A, Barsh GS, Furukawa S, Lipton JM. Inhibition of peripheral NF-kappaB activation by central action of {alpha}-melanocyte-stimulating hormone. J Neuroimmunol 1999;99:211–217.[CrossRef][Medline]
  64. Maulik N, Sato M, Price BD, Das DK. An essential role of NFkappaB in tyrosine kinase signaling of p38 MAP kinase regulation of myocardial adaptation to ischemia. FEBS Lett 1998;429:365–369.[CrossRef][Medline]
  65. Liaudet L, Pacher P, Mabley JG, Virag L, Soriano FG, Hasko G, Szabo C. Activation of poly (ADP-ribose) polymerase-1 is a central mechanism of lipopolysaccharide-induced acute lung inflammation. Am J Respir Crit Care Med 2002;165:372–377.[Abstract/Free Full Text]
  66. Rabb H, Wang Z, Nemoto T, Hotchkiss J, Yakoto N, Soleimani M. Acute renal failure leads to dysregulation of lung salt and water channels. Kidney Int 2003;63:600–606.[CrossRef][Medline]
  67. Goggel R, Hoffman S, Nusing R, Narumiya S, Uhlig S. Platelet-activating factor-induced pulmonary edema is partly mediated by prostaglandin E2, E-prostanoid 3-receptors, and potassium channels. Am J Respir Crit Care Med 2002;166:657–662.[Abstract/Free Full Text]
  68. Sun B, Fan H, Honda T, Fujimaki R, Lafond-Walker A, Masui Y, Lowenstein CJ, Becker LC. Activation of NF kappa B and expression of ICAM-1 in ischemic-reperfused canine myocardium. J Mol Cell Cardiol 2001;33:109–119.[CrossRef][Medline]
  69. Raap U, Brzoska T, Sohl S, Path G, Emmel J, Herz U, Braun A, Luger T, Renz H. {alpha}-Melanocyte-stimulating hormone inhibits allergic airway inflammation. J Immunol 2003;170:353–359.
  70. Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 2001;344:699–709.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Am. J. Physiol. Renal Physiol.Home page
H. T. Hassoun, M. L. Lie, D. N. Grigoryev, M. Liu, R. M. Tuder, and H. Rabb
Kidney ischemia-reperfusion injury induces caspase-dependent pulmonary apoptosis
Am J Physiol Renal Physiol, July 1, 2009; 297(1): F125 - F137.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
K. D. Liu
Impact of acute kidney injury on lung injury
Am J Physiol Lung Cell Mol Physiol, January 1, 2009; 296(1): L1 - L2.
[Full Text] [PDF]

Home page
 Endocr. Rev.Home page
T. Brzoska, T. A. Luger, C. Maaser, C. Abels, and M. Bohm
{alpha}-Melanocyte-Stimulating Hormone and Related Tripeptides: Biochemistry, Antiinflammatory and Protective Effects in Vitro and in Vivo, and Future Perspectives for the Treatment of Immune-Mediated Inflammatory Diseases
Endocr. Rev., August 1, 2008; 29(5): 581 - 602.
[Abstract] [Full Text] [PDF]

Home page
 CJASNHome page
K. D. Liu and M. A. Matthay
Advances in Critical Care for the Nephrologist: Acute Lung Injury/ARDS
Clin. J. Am. Soc. Nephrol., March 1, 2008; 3(2): 578 - 586.
[Abstract] [Full Text] [PDF]

Home page
 CJASNHome page
J. L. Koyner and P. T. Murray
Mechanical Ventilation and Lung-Kidney Interactions
Clin. J. Am. Soc. Nephrol., March 1, 2008; 3(2): 562 - 570.
[Full Text] [PDF]

Home page
 Am. J. Physiol. Renal Physiol.Home page
H. T. Hassoun, D. N. Grigoryev, M. L. Lie, M. Liu, C. Cheadle, R. M. Tuder, and H. Rabb
Ischemic acute kidney injury induces a distant organ functional and genomic response distinguishable from bilateral nephrectomy
Am J Physiol Renal Physiol, July 1, 2007; 293(1): F30 - F40.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Renal Physiol.Home page
A. S. Awad and M. D. Okusa
Distant organ injury following acute kidney injury
Am J Physiol Renal Physiol, July 1, 2007; 293(1): F28 - F29.
[Full Text] [PDF]

Home page
 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
S. Ota, K. Nakamura, T. Yazawa, Y. Kawaguchi, Y. Baba, R. Kitaoka, N. Morimura, T. Goto, Y. Yamada, and K. Kurahashi
High tidal volume ventilation induces lung injury after hepatic ischemia-reperfusion
Am J Physiol Lung Cell Mol Physiol, March 1, 2007; 292(3): L625 - L631.
[Abstract] [Full Text] [PDF]

Home page
 J. Am. Soc. Nephrol.Home page
T. S. Hoke, I. S. Douglas, C. L. Klein, Z. He, W. Fang, J. M. Thurman, Y. Tao, B. Dursun, N. F. Voelkel, C. L. Edelstein, et al.
Acute Renal Failure after Bilateral Nephrectomy Is Associated with Cytokine-Mediated Pulmonary Injury
J. Am. Soc. Nephrol., January 1, 2007; 18(1): 155 - 164.
[Abstract] [Full Text] [PDF]

Home page
 J. Am. Soc. Nephrol.Home page
A. Zarbock, M. Schmolke, T. Spieker, K. Jurk, H. Van Aken, and K. Singbartl
Acute Uremia but Not Renal Inflammation Attenuates Aseptic Acute Lung Injury: A Critical Role for Uremic Neutrophils
J. Am. Soc. Nephrol., November 1, 2006; 17(11): 3124 - 3131.
[Abstract] [Full Text] [PDF]

Home page
 J. Am. Soc. Nephrol.Home page
P. Devarajan
Update on Mechanisms of Ischemic Acute Kidney Injury
J. Am. Soc. Nephrol., June 1, 2006; 17(6): 1503 - 1520.
[Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
M. Vento, J. Sastre, M. A. Asensi, and J. Vina
Room-Air Resuscitation Causes Less Damage to Heart and Kidney than 100% Oxygen
Am. J. Respir. Crit. Care Med., December 1, 2005; 172(11): 1393 - 1398.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
D. Angus, A. Ishizaka, M. Matthay, F. Lemaire, W. MacNee, and E. Abraham
Critical Care in AJRCCM 2004
Am. J. Respir. Crit. Care Med., March 15, 2005; 171(6): 537 - 544.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Online Supplement
Right arrow All Versions of this Article:
200303-372OCv1
169/6/749    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Deng, J.
Right arrow Articles by Star, R. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Deng, J.
Right arrow Articles by Star, R. A.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Proc. Am. Thorac. Soc. Am. J. Respir. Cell Mol. Biol.
Copyright © 2004 American Thoracic Society