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Ann Thorac Surg 2004;77:1056-1062
© 2004 The Society of Thoracic Surgeons
a Department of Surgery, Division of Cardiothoracic Surgery, University of Washington Medical Center, Seattle, Washington, USA
Accepted for publication August 7, 2003.
* Address reprint requests to Dr Farivar, Division of Cardiothoracic Surgery, Box 356310, University of Washington Medical Center, Seattle, WA 98195, USA
e-mail: afarivar{at}u.washington.edu
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Abstract |
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, monocyte chemoattractant protein (MCP)-1, and regulated upon activation normal T cells expressed and secreted (RANTES) in LIRI.
METHODS: Left lungs of Long-Evans rats underwent normothermic ischemia for 90 minutes and reperfusion for up to 4 hours. Treated animals received anti–MIP-1, anti–MCP-1, or anti-RANTES antibodies before reperfusion. Changes in lung vascular permeability were measured with iodine 125–labeled bovine serum albumin. Neutrophil accumulation in the lung parenchyma was determined by myeloperoxidase activity, and bronchoalveolar lavage was performed to measure leukocyte cell counts. Western blots, Northern blots, and ribonuclease protection assays assessed ß-chemokine messenger RNA and protein levels.
RESULTS: Animals receiving anti–MIP-1 demonstrated reduced vascular permeability compared with controls (p < 0.001). Attenuation of permeability was less dramatic in animals treated with anti–MCP-1 and anti-RANTES antibody, which demonstrated permeability decreases of 15% and 16%, respectively (p < 0.02). Lung neutrophil accumulation was reduced in animals receiving anti–MIP-1 antibody (p < 0.005) but was unchanged in animals receiving either anti–MCP-1 or anti-RANTES. Bronchoalveolar lavage leukocyte content was also reduced by treatment with anti–MIP-1 (p < 0.003) and was unchanged in anti–MCP-1–treated and anti-RANTES–treated animals. MIP-1 treatment decreased tumor necrosis factor- messenger RNA in injured left lungs.
CONCLUSIONS: MIP-1 is functionally significant in the development of LIRI. It likely exerts its effects in part by mediating the expression of proinflammatory and antiinflammatory cytokines and influencing tissue neutrophil recruitment. MCP-1 and RANTES seem to play relatively minor roles in the development of direct LIRI.
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Introduction |
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Recent interest has focused on the role of cytokines and inflammatory peptides in the pathophysiology of lung reperfusion injury. The relevance of cytokines in mediating reperfusion injury in lung transplants has been postulated for some time [4], and prior animal studies [5, 6] suggest that interleukin (IL)-10 and platelet-activating factor may play important roles. Novel groups of cytokines, the chemokines, have been implicated in various models of inflammation and are likely involved in the development of reperfusion injury.
The chemokines are a family of chemotactic cytokines with a high degree of specificity for different subpopulations of leukocytes. Four groups of chemokines have been characterized on the basis of the structure of the peptides comprising the first conserved cysteine motif: C-C, C-X-C, C-X3-C, and C. The C-C, or ß, chemokines have 2 sequential cysteine residues and function primarily as monocyte and lymphocyte chemotactic agents. Members of this family include monocyte chemoattractant protein (MCP)-1, regulated upon activation normal T cells expressed and secreted (RANTES), and macrophage inflammatory protein (MIP)-1. The C-X-C, or , chemokines are characterized by the presence of an amino acid between the 2 cysteine residues and include powerful neutrophil chemoattractants such as IL-8, MIP-2, and cytokine-induced neutrophil chemoattractant. The 2 more recently discovered groups of chemokines include the C and C-X3-C family. These chemokines are chemotactic for T lymphocytes and monocytes and include lymphotactin (C) and neurotactin (C-X3-C).
MIP-1 is a macrophage-derived chemokine composed of 2 subunits, MIP-1 and MIP 1ß [7]. MIP-1 is predominantly chemotactic for monocytes and lymphocytes, but it also promotes neutrophil activation and chemotaxis [8]. Functional roles for MIP-1 have been demonstrated in an in vivo model of lipopolysaccharide (LPS)- and immunoglobulin (Ig)G-induced lung injury [9]. In these models, animals receiving antibody to MIP-1 had considerable decreases in lung vascular permeability and neutrophil counts in the bronchoalveolar lavage (BAL) effluent. Reperfusion injury in rat lungs has been characterized as a neutrophil-mediated tissue injury with increases in both vascular permeability and alveolar leukocyte accumulation that peak at 4 hours of reperfusion [10]. In vitro studies of hypoxic lung injury demonstrate increased levels of MIP-1 messenger RNA (mRNA) localized to monocytes and macrophages [11]. Although these observations suggest a role for MIP-1 in LIRI, no prior functional studies have been published.
Inconsistent findings regarding the role of MCP-1 in LIRI were outlined in a single publication in which treatment with anti–MCP-1 antibodies did not seem to reduce injury after 4 hours of reperfusion [10]. RANTES involvement in the development of LIRI has not been published. Using an established rat model of direct LIRI, we sought to define the function of the ß-chemokines—MIP-1, MCP-1, and RANTES—in the development of acute reperfusion injury.
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Material and methods |
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, MCP-1, RANTES, and nonspecific IgG were purchased from Peprotech Industries (Rocky Hills, NJ). All other reagents were purchased from Sigma Chemical (St. Louis, MO) unless otherwise specified.
Animal model
Pathogen-free Long-Evans rats (Simonsen Labs, Gilroy, CA) weighing 280 to 320 g were used for all experiments. The University of Washington Animal Care Committee approved all experimental protocols. All animals received humane care in accordance with the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health (National Institutes of Health publication 85-23, revised 1985).
Animals were initially anesthetized with 30 mg of intraperitoneal pentobarbital and were subsequently shaved and prepared. A 14-gauge angiocatheter was inserted into the trachea through a midline neck incision and secured with a 4-0 braided suture. Animals were then placed on a Harvard Rodent Ventilator (Harvard Apparatus Inc, Holliston, MA) with a standardized inspired oxygen content of 60% and 2 cm H2O of positive end-expiratory pressure. Maximal peak pressures were maintained at less than 10 cm H2O. All animals received 0.2 mg of atropine intramuscularly after being placed on the ventilator to maintain their heart rates during anesthesia. Dissection was conducted with an operating microscope, and a warming blanket was placed underneath the animals throughout the experiment. The animals were placed on their right sides, and a left anterolateral thoracotomy in the fifth intercostal space was performed. The left lung was mobilized atraumatically, and the inferior pulmonary ligament was divided sharply. At this time all animals received 50 U of heparin dissolved in saline (total volume, 500 µL) through a penile vein. Five minutes after heparin was administered the pulmonary hilum was occluded with a noncrushing microvascular clamp. The period of ischemia was held constant at 90 minutes. At the end of the ischemic period the clamp was removed carefully from the hilum so as not to injure any structures, and the lung was allowed to ventilate and reperfuse for up to 4 hours. Animals were administered warm subcutaneous saline 0.5 mL/h to maintain hydration during the experiment. At the end of the reperfusion period a midline incision from the neck to the pubis was created to allow access to the chest and abdominal cavities. Blood samples were obtained from the inferior vena cava just before sacrifice. The heart-lung block was rapidly excised, and the pulmonary circulation was flushed through the main pulmonary artery with 20 mL of normal saline. The lungs were then separated from mediastinal tissues and analyzed as outlined below. Time-matched control animals underwent the same procedure except that the microvascular clamp was not applied to the hilum (sham/thoracotomy alone).
To determine the function of MIP-1 on LIRI, treated animals received polyclonal rabbit anti-rat MIP 1 antibody. A total of 250 µg of antibody was dissolved in 500 µL of sterile phosphate-buffered saline just before administration. It was then injected through a penile vein 5 minutes before removal of the vascular clamp from the hilum. Anti–MCP-1, anti-RANTES, and nonspecific IgG were administered at similar doses in the same manner.
Lung permeability index
To quantitate lung vascular injury secondary to ischemia and reperfusion, a permeability index (PI) was measured. Iodine 125 (125I)-radiolabeled bovine serum albumin (BSA) was obtained from NEN Life Sciences (Boston, MA). Before use of the 125I BSA in vivo, serial dilutions were performed to obtain an activity of approximately 800,000 counts per minute (cpm). This volume of 125I BSA was then brought to a final volume of 500 µL in a 1% BSA/phosphate-buffered saline solution. Five minutes before removal of the hilar clamp or at an equivalent time in sham animals, the 125I BSA mix was intravenously injected. Immediately before sacrifice of the animals, 1 mL of blood was drawn from the inferior vena cava. The heart-lung block was then excised and flushed as described previously. The counts were quantitated in the left lung and inferior vena cava blood sample by using a scintillation counter. The PI was then expressed as the ratio of the counts per minute in the left lung to the counts per minute in 1 mL of inferior vena caval blood.
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Four different groups were generated. Negative controls were those that did not undergo any surgical manipulation. Sham/thoracotomy-alone controls were placed on the ventilator and had a left thoracotomy and up to 5.5 hours of mechanical ventilation. An ischemia-only group had a thoracotomy, and the left hilum was occluded for 90 minutes. These animals were sacrificed before any reperfusion. The final group, the positive controls, underwent the full experimental protocol of 90 minutes of ischemia followed by 4 hours of reperfusion. All groups contained at least 4 animals.
Myeloperoxidase assay
The myeloperoxidase (MPO) assay was used to quantitate lung tissue neutrophil accumulation. Lungs for MPO analysis were harvested in a manner similar to that described previously. The lungs were homogenized for 60 seconds in a solution of 0.5% hexadecyltrimethylammonium bromide and 5 mmol/L ethylenediaminetetraacetic acid in 50 mmol/L potassium-phosphate buffer (pH 6.0). Samples were then sonicated for 40 seconds in four 10-second bursts. The homogenized tissue was maintained on ice between all tissue processing periods. Samples were centrifuged at 2,300 rpm for 30 minutes at 4°C. Assay buffer was composed of 0.0005% H2O2 and 0.167 mol/L O-dianisidine dihydrochloride in 100 mmol/L potassium phosphate buffer (pH 6.0). A total of 50 µL of each sample was mixed with 1.45 mL of assay buffer, and the change in absorbance at 460 nm over 1 minute was recorded. MPO activity was measured in lungs from unmanipulated controls; from animals that underwent 90 minutes of ischemia and 0, 1, 2, 3, and 4 hours of reperfusion; and from animals treated with antibodies to the ß-chemokines at 4 hours of reperfusion. Additional animals, separate from prior studies outlined in this article, were generated for these studies and numbered at least 4 per group.
BAL cell counts
Additional animals underwent BAL at the time of sacrifice. The heart-lung block was not flushed. By use of the 14-gauge angiocatheter placed for ventilation, the lungs were lavaged individually with 3 mL of cold sterile saline. To facilitate individual lung BAL analysis, the contralateral hilum was occluded with a curved clamp. At least 80% of the instilled fluid was recovered from each lung BAL. This fluid was centrifuged (1500 rpm x 8 minutes at 4°C) to pellet the cells in the lavage fluid. The pellet was resuspended in 10 mL of sterile water to lyse red blood cells. This fluid was again centrifuged (1500 rpm x 8 minutes at 4°C), the supernatant was discarded, and the cells were counted with a hemacytometer (Hausser Scientific, Horsham, PA).
Western blot analysis
Lungs were homogenized in 10 mL of solution containing 10 mmol/L 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (pH 7.9), 150 mmol/L NaCl, 1 mmol/L ethylenediaminetetraacetic acid, 0.5 mol/L phenylmethylsulfonyl fluoride, 0.6% NP-40, and a protease inhibitor cocktail. The homogenate was incubated on ice for 5 minutes, and 1-mL aliquots were placed into microfuge tubes for analysis. The remaining sample was stored as whole-cell lysates at 4°C. Samples were centrifuged at 14,000 rpm for 10 minutes at 4°C. The pellet was discarded, and the supernatant protein concentration was determined by using the bicinchoninic assay (Pierce, Rockford, IL). A total of 40 µg of protein was loaded on sodium dodecyl sulfate polyacrylamide gel electrophoresis gels (12%) and run at 100 V for 2 hours. The gels were then transferred to a polyvinylidene difluoride membrane and incubated with anti–MCP-1, anti-RANTES, or anti–MIP-1 polyclonal antibodies at a 1:1,000 dilution overnight. A horseradish peroxidase–conjugated secondary antibody was applied for 1 hour, and the proteins were visualized by using Pierce Supersignal reagents (Amersham Biosciences, Piscataway, NJ) and autoradiography.
Northern blot analysis
Additional lungs were harvested at the end of the experimental protocol and snap-frozen in liquid nitrogen. RNA was extracted by using a phenol-chloroform extraction method as previously described. Cytoplasmic RNA was fractionated electrophoretically in a 1% formaldehyde gel and transferred to a nylon membrane (Zetabind; Cuno Inc, Meriden, CT). By using plasmids containing the MIP-1 clone, phosphorus 32 (32P)-labeled deoxycytidine triphosphate probes were generated by polymerase chain reaction with the MIP-1–specific oligoprimers. Radioactivity of the probes was determined by scintillation counting, and 1.5 x 107 cpm were applied to the Northern blot; hybridization was performed at 65°C for 16 hours. Autoradiography was performed at -70°C on Kodak (Rochester, NY) X-OMAT-AR film.
Ribonuclease protection assay
Lung RNA was isolated in guanidine thiocyanate, with 2 rounds of acid phenol and chloroform extraction and alcohol precipitation. RNA integrity was confirmed by agarose gel electrophoresis and quantitated by optical density measurements (260 nm). RNA from each rat was evaluated by using the Riboquant system (PharMingen, San Diego, CA). Rat template rCK1 was used for detection of cytokines. In vitro transcription was performed in transcription buffer supplemented with [-32P]uridine triphosphate (3,000 Ci/mmol; Amersham Biosciences) and T7 RNA polymerase. After deoxyribonuclease I treatment, the riboprobe was isolated by phenol/chloroform extraction and ammonium acetate/ethanol precipitation, and labeling efficiency was determined by measuring Chernokov activity in a scintillation counter. Each riboprobe was diluted to the optimal activity defined by the manufacturer, added to 20 µg of kidney RNA, heated to 90°C, allowed to cool to 56°C, and annealed overnight. After ribonuclease and proteinase K treatment, protected RNA hybrids were purified by phenol/chloroform extraction and ammonium acetate/ethanol precipitation and separated by electrophoresis on 5% polyacrylamide/8 mol/L urea gels. Gels were dried and subjected to autoradiography by using Kodak Biomax MS2 film.
Ribonuclease protection assays were performed on lung extracts from 3 experimental groups, including the unmanipulated negative controls, animals that underwent 90 minutes of ischemia followed by 4 hours of reperfusion, and animals that received antibody to MIP-1 at 4 hours of reperfusion. Both left and right lungs were evaluated in all experimental groups.
Statistical analysis
All data are presented as mean ± standard error of the mean unless otherwise designated. Comparisons between individual groups were made with a 2-tailed Student's t test, and statistical significance was defined for all tests as a p value less than 0.05.
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Results |
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There was no significant difference in PIs among animals receiving phosphate-buffered saline (0.75 ± 0.01) or nonspecific IgG (0.77 ± 0.02) at 4 hours of reperfusion when compared with positive control animals. Animals receiving antibody to MIP-1 (0.52 ± 0.02) had a significant decrease in permeability at 4 hours of reperfusion when compared with positive controls; this represented a 37% decrease in lung injury (p < 0.001). Animals receiving anti-RANTES (0.62 ± 0.01) and anti–MCP-1 (0.65 ± 0.02) antibodies demonstrated modest 16% and 15% reductions in vascular permeability, respectively, in comparison to positive controls (Table 1), and these differences were statistically significant (p < 0.02) on both accounts.
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had a 42% decrease in MPO activity (0.26 ± 0.02) at 4 hours of reperfusion compared with positive controls (Table 2). This reflected a significant reduction (p < 0.02) in lung tissue neutrophil accumulation. Insignificant reductions in tissue neutrophil accumulation were evident in animals receiving antibody to either MCP-1 (0.40 ± 0.02) or RANTES (0.39 ± 0.03).
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In animals treated with antibody to MIP-1, there was a significant decrease (p < 0.003) in alveolar leukocyte cell counts (100 x 105 ± 6 cells) in comparison to the positive controls (156 x 105 ± 9 cells; Table 3). No significant difference in BAL cell counts was evident between animals receiving anti-RANTES or anti–MCP-1 antibodies and positive control animals.
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in unstimulated left lungs or any of the reperfusion time points up to 2 hours. However, MIP-1 protein was present by 3 hours of reperfusion in injured left lungs, and strong expression was evident at 4 hours of reperfusion. MCP-1 and RANTES protein are not detected in negative controls or lungs at 1, 2, or 3 hours of reperfusion but are seen at 4 hours of reperfusion (Fig 1).
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messenger RNA appeared within 30 minutes of reperfusion and was present throughout the reperfusion period (Fig 2). There was no message expression in the negative control animals.
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, and IL-2). In injured left lungs from animals treated with anti–MIP-1 antibodies, mRNA for IL-4 was accentuated, whereas mRNA for TNF- and the T helper type 1 cytokine IL-2 was sharply reduced (Fig 3). The right lung in this experimental group was notably less active.
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Comment |
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TopAbstractIntroductionMaterial and methodsResultsCommentReferences |
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is unique among the ß-chemokines in that it is also chemotactic for neutrophils. Initial studies indicated that MIP-1 was a potent chemoattractant for both CD4 and CD8 lymphocytes [11]. Subsequently, other investigators demonstrated in vitro that MIP-1 was a potent macrophage chemoattractant and activator [12]. These activities of MIP-1 are currently being investigated in human trials, where a genetically engineered analogue of MIP-1 has demonstrated safety in clinically relevant monocytosis [13]. Experiments in a murine model of allergic peritonitis have confirmed that MIP-1 is important in mediating neutrophil recruitment [14]. In addition, the influx of neutrophils observed in LPS- and IgG-induced lung injury is attenuated in animals receiving antibody to MIP-1 [9]. The facts that MIP-1 is upregulated after oxidative stress, regulates nonischemic lung injury, and influences tissue neutrophil recruitment are all consistent with the positive findings in this study.
MCP-1 and RANTES have also been studied in models of acute lung injury and do not seem to play a functional role in the development of acute lung injury [15]. Unlike MIP-1, MCP-1 and RANTES do not seem to have any role in neutrophil chemotaxis. Previous work has shown that in models of IgG immune complex alveolitis and LPS-induced acute lung injury, MCP-1 and RANTES protein are secreted in appreciable amounts after these stressors but that antagonization of their function had no effect on depressing inflammatory responses or reducing several indicators of acute lung injury [16]. Another study focused on whether lung vascular permeability was enhanced after the administration of recombinant formulations of MCP-1 and RANTES and found no marked alteration relative to control animals. It is therefore not surprising that antagonizing their function with antibodies did not affect tissue MPO content or BAL leukocyte counts after ischemia and reperfusion. One study, using a similar model of rat LIRI, suggested that MCP-1 blockade was protective at 30 minutes of reperfusion but not at 4 hours of reperfusion [10]. The importance of these results is difficult to appreciate, particularly in light of the fact that both RANTES and MCP-1 are detected weakly at 4 hours of reperfusion on the Western blots of injured left lungs. Eppinger and colleagues' [10] findings in anti–MCP-1–treated animals could be explained by the fact that they demonstrated more severe changes in lung vascular permeability at 30 minutes of reperfusion than at 4 hours. The protective effects of anti–MCP-1 antibodies after only 30 minutes of reperfusion are difficult to explain given that MCP-1 protein was not detectable at this early time point on Western blots.
A vigorous neutrophilic infiltrate and a considerable change in lung vascular permeability characterize LIRI in this experimental model. Depletion of neutrophils is associated with amelioration of this injury. The role of one chemokine, IL-8 [17, 18], has been demonstrated in LIRI in rabbits. Its role cannot be investigated in rats because it has not yet been cloned. Furthermore, the role of other chemokines has not been studied in in vivo lung ischemia-reperfusion models. Of the ß-chemokines, MIP-1 is particularly relevant because of its role in neutrophil chemotaxis, and in vitro studies suggest that oxidative stress upregulates MIP-1 mRNA production in cultured alveolar macrophages [19]. Additionally, clinical studies in human liver transplantation indicate that MIP-1 protein levels are increased immediately after graft reperfusion [20].
Our data support a functional role for MIP-1 in an in vivo model of oxidative stress. Lung injury, measured with PI, was decreased by 37% in animals receiving antibodies to MIP-1. This amelioration of lung vascular injury is similar to the 42% decrease in PI seen with MIP-1 blockade in IgG- and LPS-induced lung injury [9]. The relative significance of this degree of protection is difficult to determine. In this same model, blockade of TNF- with a specific polyclonal rabbit anti-rat TNF- antibody resulted in a 45% decrease in left lung permeability [21]. Considering that TNF- is considered one of the primary proinflammatory cytokines involved in reperfusion injury, the 37% protection seen with MIP-1 blockade is notable.
The BAL cell counts demonstrating amelioration of injury seen with MIP-1 blockade are associated with a reduction in neutrophil influx, further supporting the notion that MIP-1 functions in vivo as a neutrophil chemoattractant [8]. MPO activity, a marker for neutrophil influx and activity in tissue, was decreased by 42% in animals treated with antibodies to MIP-1, in comparison to positive control animals. Therefore, MIP-1 is functionally important in the development of acute reperfusion injury and exerts its effects partly through neutrophil chemoattraction.
The slight decrease in permeability seen with MCP-1 and RANTES treatment may be related to the polyclonal nature of the antibodies or to the fact that they may alter a later-occurring second wave of cytokine release. It is apparent from the MPO and BAL data that these 2 chemokines play a small role in neutrophil recruitment, and they seem to be expressed late during reperfusion. The antibodies to MCP-1 and RANTES may bind to epitopes for other chemokines and decrease injury without effecting neutrophil recruitment.
Although the cellular events mediating MIP-1 activation in LPS-induced inflammation have been studied [22], the mechanisms involved in chemokine expression and activation after hypoxic stress have not yet been elucidated. The alveolar macrophage is likely the central cell mediating the inflammatory response in lung inflammation. In vitro studies have revealed that MIP-1 can induce cytokine production by macrophages [12], and this observation may be relevant to the differences seen in the ribonuclease protection assay between the positive control animals and those receiving antibody to MIP-1. It seems that animals treated with MIP-1 antibody demonstrate a decreased expression of mRNA from TNF- and IL-2, both of which are known proinflammatory mediators. In addition, expression of IL-4 mRNA was enhanced in animals receiving MIP-1 antibody treatment. We have previously shown that exogenous IL-4 is protective against the development of LIRI in this model [23], and, therefore, augmenting the expression of this antiinflammatory peptide would provide further indirect protection against lung injury.
There are some limitations inherent to this model; these include the fact that this is a small-animal, hilar clamp model of LIRI. A large-animal, orthotopic lung transplantation model would be more clinically relevant and would afford us the ability to measure physiologic variables of the reperfused lung, a difficult task to perform in rodent models.
In conclusion, MIP-1 seems to be functionally significant in the development of LIRI in a warm in situ hilar clamp model. MIP-1 likely exerts its effects in part by mediating the expression of proinflammatory and antiinflammatory cytokines and by influencing tissue neutrophil recruitment. MCP-1 and RANTES, however, seem to play relatively minor roles in the development of direct LIRI. Future studies involving other members of the ß-chemokine family, including MCP-2, MCP-3, MCP-4, eotaxin, MIP-1ß, MIP-1
, and thymus and activation-regulated chemokine, are warranted as we attempt to define the roles of these complex and interrelated proteins in models of lung reperfusion injury.
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References |
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and MIP 1ß. Science 1993;260:355-357. mRNA by oxidative stress. J Biol Chem 1996;275:5878-5883.
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