Modulation of Postsurgical Macrophage Postsurgical Polymorphonuclear SETSUO KURAOKA, Livingston





Biology Laboratory, Department of Obstetrics and Gynecology, University of Southern School of Medicine, 1321 North Mission Road, Los Angeles, California 90033 Submitted

for publication



2, 1990

blasts [l, 21. Postsurgical macrophages are a primary source of arachidonic acid metabolites, neutral proteases, and protease inhibitors which modify tissue repair cell proliferation, differentiation, and the production of extracellular matrix. Infiltration of polymorphonuclear leukocytes (PMNs) into the peritoneal cavity occurs rapidly after surgical trauma. PMNs as well as macrophages act as scavengers through phagocytic activity. Several cytokines, such as interleukin-1 (IL-l), y-interferon, and interleukin-4, affect macrophage function. For example, IL-l stimulates plasminogen activator activity and acid-labile inhibitors in the spent media of postsurgical macrophages [3]. In the absence of infection, the number of PMNs in the peritoneal cavity is reduced by Day 3 after surgery so the principal leukocyte remaining is the macrophage. Surgical trauma appears to prime the resident macrophages which then differentiate to promote wound healing. Since PMNs are the major cellular components (i.e., leukocytes) at the wound site in the immediate postoperative interval, this study assessedthe influence of PMNs on macrophage function.

Surgical trauma to the peritoneum, in the absence of infection, elicits a rapid and transient influx of polymorphonuclear leukocytes (PMNs) into the peritoneal cavity prior to the accumulation of macropbages. The aim of this study was to characterize the effects of these PMNs on macrophage function in the early postsurgical period. Rabbits underwent intestinal reanastomosis and peritoneal exudate cells were collected at various times after surgery. Macrophage-enriched preparations were incubated with spent media from cultures of PMNs obtained at the corresponding times after surgery. Superoxide anion (0,) release by macrophages in response to phorbol myristate acetate was determined by cytochrome c reduction. Fibrinolytic and protease inhibitory activities in macrophage-spent media were also evaluated. The release of 0, had already increased at 2 hr, reached peak levels at 6 hr, and decreased by 24 hr after surgery. Spent media from PMNs harvested 6 hr after surgery suppressed, whereas spent media from postsurgical 12- or 24-hr PMNs increased 0, release from macrophages harvested at 6 and 12 hr after surgery. PMN-spent media had no effect on the secretion of plasminogen activator (PA) from macrophages harvested within 12 hr after surgery. In contrast, PA activity in the spent media from macrophages harvested 24 hr after surgery was elevated after exposure to PMNspent media. PA inhibitory activity was reduced in macrophage-spent media at 2 hr after surgery and increased by 24 hr, while PMN-spent media had no effect on the level of PA inhibitory activity. Thus, soluble factors secreted into the culture medium by PMNs modulate macrophage function as soon as 6-12 hr after surgery. 0 1992 Academic Press, Inc.



Animals and Surgery New Zealand white female rabbits (2.5 kg) underwent a lower midline laparotomy, followed by resection and reanastomosis of their ileum with 6-O Vicryl sutures (Ethicon, Raritan, NJ) under the influence of Rompun (25 mg/kg, Byvet Division Miles Laboratories, Inc., Shawnee, KS) and ketamine hydrochloride (130 mg/kg, Park-Davis, Morris Plains, NJ) anesthesia. The abdominal wall was closed in two layers with 3-O Dexon sutures (Davis-Geck, Monti, PR). Throughout the postsurgical interval, rabbit chow (Purina) and water were provided ad Zibitum. All animals tolerated the surgery well. No perioperative antibiotic therapy was used. At various times after surgery, rabbits were sacrificed by pentobarbiturate overdosage to collect peritoneal exudate cells by lavage of the peritoneal cavity with 100 ml of phosphate-

INTRODUCTION Postsurgical repair of the peritoneum involves a variety of cellular responsesbetween macrophages and fibro-

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buffered saline (PBS, pH 7.4) containing heparin (10 IU/ml; Elkis-Sinn, Inc., Cherry Hill, NJ). Resident control macrophages were also collected from non-surgical rabbits in the same manner. Cell Preparation Cells collected from the peritoneal cavity were centrifuged at 200g for 15 min and pellets were washed with 10 ml of PBS and recentrifuged. Cells were resuspended in 10 ml of PBS and layered over 10 ml of cold isotonic Percoll/PBS solution (60%; density, 1.084 g/ml) and centrifuged at 400g for 20 min. Macrophages were collected from the interface/intermediate layer and washed two times with 10 ml of Roswell Park Memorial Institute (RPMI) 1640 medium (GIBCO, Grand Island, NY), which resulted in a cell preparation of over 90% macrophages and less than 5% PMNs as determined morphologically. Cells contained greater than 90% viability determined by trypan blue exclusion. Quadruplicate wells with 5 X lo5 cells/well in 48-well plates (Costar, Cambridge, MA) were cultured in 1 ml of RPM1 1640 medium containing antibiotics (penicillin, 100 mIU/ml; streptomycin, 60 pg/ml, and amphotericin B, 2.5 pg/ml) and 10% fetal calf serum (Irvine Scientific, Santa Ana, CA). Cells were cultured for 3 hr to allow attachment in a humidified atmosphere of 5% CO,, 95% air at 37°C. After 3 hr incubation, each well was washed three times with PBS, and the adherent macrophages were assayed. Pellets from the Percoll discontinuous gradient centrifugation, containing the PMNs, were collected and contaminating erythrocytes were lysed by exposure to sterile distilled water for 40 set followed by the addition of 10X PBS to restore isotonicity. Resuspended cells were again centrifuged at 200g for 10 min. The cellular composition was approximately 70% granulocytes and 30% mononuclear cells. Cell viability as determined by the trypan blue exclusion method was consistently found to be about 70% before and after cell culture. These cells were resuspended in either 10 ml of RPM1 1640 medium containing 0.2% lactalbumin hydrolysate (LH) with antibiotics or Earle’s balanced salt solution (EBSS), at a concentration of 8-16 X lo4 cells/ml. These PMN-enriched cultures were incubated for 4 hr in a humidified atmosphere of 5% CO, and 95% air at 37’C. The PMN-spent media (two types as described above) were harvested and centrifuged at 200g for 10 min, and each supernatant was then added to the corresponding macrophage culture wells. Superoxide




The release of 0; by peritoneal macrophages in response to phorbol myristate acetate (PMA; Sigma, St. Louis, MO) was measured at various times after surgery by the quantitation of superoxide dismutase (SOD, from bovine erythrocytes, Sigma) -inhibitable reduction of ferricytochrome c (Cyt c, Type III, Sigma) [4]. After 3 hr


53, NO.



incubation to allow adherence, the wells containing macrophages were rinsed three times with warm PBS. Three hundred microliters of fresh EBSS or PMN-spent media from cells harvested at various postsurgical times was added to the macrophage monolayers. Seven hundred microliters of a Cyt c solution containing PMA in EBSS was then added to each well in the presence or absence of SOD. Each reaction was run in duplicate. As controls for the addition of media to the 0, assay, PMN-spent media was tested. In addition, 0, levels in macrophage-free wells were examined and used as background. The final concentration of each reagent was as follows: 80 PM Cyt c, 0.5 pg/ml PMA, and 100 pg/ml SOD. After 1 hr incubation, the supernatant absorbance at 550 nm was measured against reference samples of Cyt c using a Beckman DU-7 spectrophotometer (Fullerton, CA). Adherent cells were washed twice with PBS and protein was determined by the BCA protein method (Pierce, Rockford, IL). In this assay, cellular protein concentrations ranged between 10 and 30 pg/well. Absorbances were converted to nanomoles of Cyt c reduced by employing an extinction coefficient of 2.1 X lo4 M-’ cm-’ [5]. Data were then expressed as nmoles Cyt c reduced per milligram of cell protein. Plasminogen


(PA) Activity


Macrophage monolayers from the above superoxide anion assays were incubated with 300 ~1 of the various postsurgical PMN-spent media and 700 /*l of fresh RPM1 media containing 0.2% lactalbumin hydrolysate. As media controls, postsurgical macrophages were exposed to fresh RPM1 1640 containing 0.2% LH in lieu of PMN-spent media. These cultures were incubated at 37°C in 5% CO2 and 95% air for 48 hr. After this incubation, a 0.5-ml aliquot of macrophage-spent media was adjusted to pH 2-3 with 1 N hydrochloric acid and stored overnight at 4°C (acid treatment) and then neutralized using 1 N sodium hydroxide. This acid treatment was used to inactivate acid labile protease inhibitors. PA activity in the macrophage-spent media (with or without acid treatment) was determined using a modified indirect solid-phase radiometric assay [6]. The reaction mixture contained 100 ~1 of “‘I-fibrinogen-coated latex beads suspended in 0.05 M Tris-HCl, 0.1 M NaCl, 0.01% Tween 80 (TBS-Tw80 buffer, pH 7.5) containing 0.1% unlabeled fibrinogen (Sigma), 100 ~1 of plasminogen (200 /*g/ml, Sigma), and loo-p1 sample. Using urokinase (MW 54,000 Calbiochem, La Jolla, CA) as a standard, the reaction mixture was incubated for 2 hr in a 37°C in a shaking water bath, followed by the addition of 300 ~1 of 0.05 M epsilon-aminocaproic acid (Calbiochem, La Jolla, CA) and centrifuged at 700g for 10 min. A 200-~1 aliquot of supernatant was counted in a gamma counter (Beckman, Fullerton, CA) to measure the plasminogendependent release of degradation products of ‘251-fibrinogen. Each sample was assayed in duplicate. No plasminogen-independent activity was observed.







Cellular Accumulation

after Surgery

The cellular population after intestinal surgery is shown as Fig. 1. After lavage of the peritoneal cavity by 100 ml of PBS, peritoneal exudative cells were classified by Wright’s staining. PMN influx into the peritoneal cavity peaked at 6 hr after surgery and gradually decreased thereafter. The number of macrophages continued to increase at 24 hr after surgery. I

R246 12 24 POSTSURGICAL TIME (hr) in the abdomiFIG. 1. The time course of exudate cell appearance nal cavity after peritoneal surgery. The peritoneal cavity was lavaged with 100 ml PBS and cell types were determined by Wright’s staining. Data points for resident (R), 2 and 4 hr represent the mean value of four rabbits per observation and five rabbits per observation at 6, 12, and 24 hr, respectively. (0) Total cell number, (0) macrophages, (x) polymorphonuclear leukocytes.



DNA content of the adherent cell layers was determined using the enhancement of fluorescence which accompanied bis-benzimidazole binding to DNA [7]. One milliliter of PBS containing 1 pg/ml bis-benzimide (Boehringer-Mannheim, Germany) was added to each macrophage containing well and sonicated. Quantitation of fluorescence was performed using an Aminco spectrofluorometer (Aminco Bowman, Urbana, IL) with an excitation wavelength of 356 nm and an emission wavelength of 458 nm. Calf thymus DNA (Sigma) was used as standard. In this assay, the fluorescent emission was linear between 0.6 and 20 pg DNA/ml. PA activity of the medium with or without acid treatment was expressed as milliPlough units per microgram of DNA (mPU/pg DNA). PA Inhibitory





The release of 0, from postsurgical macrophages is shown in Fig. 2 with reagent alone (controls at each postsurgical time) or after incubation with PMN-spent media. The release of 0, from macrophages without PMN-spent media (controls) was markedly elevated at 2 hr after surgery over the resident control (84 + 33 nmol Cyt c reduced/mg protein), reached a maximal level at 6 hr after surgery (473 + 96 nmol Cyt c reduced/mg protein), and then decreased to resident levels by 24 hr after surgery. After exposure to PMN-spent media, the greatest variation in the release of 0; was observed with 6 and 12 hr postsurgical macrophages. Postsurgical 6 hr PMN-spent media suppressed 0; release compared to a stimulatory effect by 12 and 24 hr PMN-spent media.



0 Hr


24 Hr


Standard urokinase (UK, 100 mPU/ml in TBSTw80) was mixed with an equal volume of sample and incubated in a polypropylene culture tube for 1 hr in a 37°C water bath. The PA activity in the samples was determined as above. Recovered UK activity was corrected for endogenous activity and expressed as a percentage inhibition of added UK (SPAI). Statistical



Data were initially analyzed by Rankit analysis to determine the distribution and then by Kruskall-Wallis one-way analysis of variance to compare the populations. The difference within the groups was examined by the Mann-Whitney U test. Results are presented as means f SEM.

cm PMN CONDITIONED MEDIA (hr) FIG. 2. Superoxide anion production by postsurgical macrophages in the presence or absence of spent media from polymorphonuclear cell cultures. Peritoneal exudate cells were collected at various times after surgery and cultured for 3 hr. Adherent macrophages were incubated with or without PMN-spent culture media obtained at various postsurgical times. The release of superoxide anion in response to phorbol myristate acetate was determined as superoxide dismutase-inhibitable cytochrome C reduced per milligram of cell protein in 1 hr at 37°C. Macrophage postsurgical time points of 0,2, and 4 hr represent the mean ? SEM of four rabbits each. Five rabbits per data point were used for 6,12, and 24 hr macrophage postsurgical time points. (C) Macrophages cultured in buffer; macrophages cultured with spent media of PMN harvested 6 hr after surgery (IV = 6); spent media of PMN harvested 12 hr after surgery (N = 12); spent media of PMN harvested 24 hr after surgery (N = 24). *P i 0.05, **P -e 0.01.







2 Hr

4 Hr

6 Hr

12 Hr


24 Hr


z 2 4




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tity of standard urokinase to the spent media and assaying for PA activity. The PA levels were then corrected for endogenous PA activity and the results were expressed as a percentage inhibition of added standard (Fig. 4). At 2 hr after surgery, PA inhibitory activity from macrophages was significantly suppressed. PA inhibitory activity then gradually increased by 24 hr after surgery, which was significantly higher than resident levels. PMN-spent media had little or no effect on the secretion of PA1 activity by postsurgical macrophages. DISCUSSION





PMN CONDITIONEO MEDIA (hr) FIG. 3. Plasminogen activator activity of postsurgical macrophage-spent media is shown. At various postsurgical times, macrophages were collected and cultured for 48 hr in the presence or absence of polymorphonuclear cell-spent media. The secretion of plasminogen activator activity was measured by a modified indirect solid-phase radiometric assay and expressed as mPU/pg DNA of adherent cells. Acid treatment was performed to remove the acid labile inhibitors in the sample. Each data point represents the mean + SEM from three to five rabbits (same as Fig. 2 legend). (0) Without acid treatment, (0) after acid treatment, other symbols are the same as in Fig. 2.

PMN-spent media assayed as a control showed lessthan 0.3 nmole Cyt c reduced/ml, which was insignificant. PA Activity Levels of PA activity from resident (control) and postsurgical macrophages in the presence or absence of PMN-spent media with and without acid treatment of the sample medium are shown in Fig. 3. Spent media from control macrophages without exposure to PMNspent media contained low levels of PA activity with no significant differences observed with the various postsurgical times. PMN-spent media had no effects on secretion of PA activity from macrophages obtained within the first 12 hr after surgery. However, macrophages collected at 24 hr after surgery were significantly affected by exposure to PMN-spent media. The level of PA activity in the culture supernatants from macrophages harvested during the initial 12-hr period was essentially unchanged by acid treatment. However, control-spent media from macrophages harvested 24 hr after surgery with and without exposure to 6 and 12 hr PMN-spent media contained elevated levels of PA activity after acid treatment. In addition, exposure of macrophages harvested 24 hr after surgery to PMN-spent media elevated the level of PA activity. The PA activity of PMN-spent media (media control) was not detectable. PAI Activity The level of PA1 activity secreted into macrophagespent media was determined by adding a known quan-

Previously, the cellular events which promote peritoneal tissue repair after surgical injury were described [8, 91. After peritoneal injury, bleeding and coagulation are the first obligatory stages in the healing process which are followed by a partially identified sequence of humoral responses and cellular interactions occurring at the wound site. Thereafter, an acute PMN-mediated inflammatory reaction occurs, even in the absence of any apparent bacterial contamination, and is followed by the accumulation of large mononuclear cells, mainly macrophages. These recruited macrophages play a central role in postoperative repair through modulation of the fibrinolytic process as well as tissue repair cell (mainly fibroblasts) proliferation and extracellular matrix secretion. The major cellular components which appear early at the wound site after surgery are PMNs and then macrophages. Here, we partially characterized the functional activity of macrophages harvested up to 24 hr after surgery and the response of these early postsurgical macrophages to PMN-spent media. This study showed that resident peritoneal macrophages were immediately primed by surgical injury, and that primed macrophages


8o 1 OHr






12 Hr

24 Hr

60 H




FIG. 4. Plasminogen activator inhibitor activity in macrophagespent media is shown. Standard urokinase (UK; 50 mPU/ml final concentration) was incubated with the macrophage-spent media and recovered UK activity was calculated and converted to percentage inhibition of primary activity. Each data point represents the mean + SEM from three to five rabbits (same as Fig. 2 legend). Each symbol is the same as in Figs. 2 and 3.





released 0, in response to PMA from early postsurgical times. The increased release of 0, in response to PMA was present as early as 2 hr after surgery, rapidly increased to a maximum by 6 hr, and then decreased by 24 hr. Previous studies showed chemically activated macrophages had a greater potential to release 0; than resident macrophages after priming by the triggering agent PMA [lo, 111. In our previous report, postsurgical macrophages released 0, even without a triggering agent at postsurgical times such as Day 5 after surgery [12]. Thus, surgical injury enhances macrophage function. The effect of PMN secretory products upon the release of 0; from macrophages harvested at various times after surgery was examined. PMN-spent media harvested 6 hr after surgery reduced 0, release by macrophages harvested at 6 and 12 hr after surgery. However, PMN-spent media 12 and 24 hr after surgery increased the 0, release of the same postsurgical macrophages. Secretory products of PMN modified 0, release by the macrophages, apparently acting both as stimulator and suppressor depending on the postsurgical time. Previously, we showed 0, release from macrophages collected without Percoll separation, in which the 0, release gradually increased during the early postsurgical days without achieving a peak within 24 hr of surgery [13]. As a mixed culture of macrophages and PMN, peritoneal exudate cells obtained early (2 days or less) after surgery did not release 0, to the same extent as the purified macrophages from the same postsurgical time period. This study showed that PMN-spent media suppressed 0, release of the macrophages even before the earliest time point studied (6 hr after surgery). Tsukamoto et al. [14] found that supernatants of macrophage cultures stimulated by lipopolysaccharide contained significantly higher levels of 0, generating potential when coincubated with PMNs. Together, these findings indicate that macrophages may autoregulate their metabolic pathway relative to respiratory burst activity. The secretion of plasminogen activator activity from postsurgical macrophages collected within 24 hr after surgery was markedly decreased. This reduction in PA activity by postsurgical macrophages early after surgery may be the result of inhibitors produced in the local environs. Early secretion of inhibitors of fibrinolysis may be instrumental in facilitating the deposition of fibrin during the early stages of wound repair [ 151. Using an abraded rabbit uterine horn model, we found that secretory products in the PMN-spent media increased the secretion of PA activity by macrophages harvested at 24 hr after surgery. However, these factors did not affect the secretion of PA activity by macrophages harvested 12 hr after surgery. Macrophage secretion of PA inhibitory activity (PAI) gradually increased 12 hr after surgery and was not affected by coincubation with PMNspent media. In this study, the level of PA activity in the culture medium of macrophages from nonsurgical rabbits was



lower than that measured in previous studies. This may be due to the short exposure of these cells to PMA during the assessment of 0,. Although previous studies in the literature showed that PMA elevated PA secretion by endothelial cells and macrophages, it may be that brief exposure to PMA followed by a prolonged culture in the absence of PMA led to the observed reduction in PA activity. In this regard, these studies examined the effects of PMN-spent media on the secretion of PA by macrophages that previously underwent two potential stimuli, i.e., surgical insult and PMA stimulation. While this adds a confounding factor to the interpretation of these results, the fact that PMN-spent media affected even PMA-stimulated macrophages harvested 24 hr after surgery indicates that there are potent modulators of macrophage function secreted by postsurgical PMNs. Previous studies evaluated the effect of cytokines such as IL-l, IL-6, TNFa, GM-CSF and a series of interferons on the macrophage cytotoxic/cytostatic activities, catabolic activities, and fibroproliferative activity [17, 181. Macrophages, T lymphocytes, endothelial cells, and fibroblasts produce some of these cytokines and probably interact with one another. We previously reported that human recombinant IL-l stimulated the release of PA activity and acid labile protease inhibitors by postsurgical macrophages in a concentration-dependent manner [3]. However, the effects were attenuated in early postsurgical macrophages. Although resident macrophages had a high sensitivity to exogenous IL-l, macrophages harvested at postsurgical Day 1 had little or almost no responsivity to physiological concentrations of IL-l. Although secretory products from postsurgical PMNs are not all characterized, they appear to mediate many but not all macrophage functions after surgery. In summary, postsurgical macrophages appear to rapidly alter their metabolic functions including production of 0,) PA inhibitory activity, and PA within 24 hr after surgery. Thus, postsurgical macrophages react to factors secreted by PMNs in various ways depending upon their functional differentiation early after surgery. ACKNOWLEDGMENT The authors manuscript.





for her diligent


of the


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Modulation of postsurgical macrophage function by early postsurgical polymorphonuclear leukocytes.

Surgical trauma to the peritoneum, in the absence of infection, elicits a rapid and transient influx of polymorphonuclear leukocytes (PMNs) into the p...
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