Cecal Ligation And Puncture Rat Research Articles

Betulinic acid reduces inflammation in rats with sepsis‐induced myocardial dysfunction by inhibiting TLR4/MyD88/NF‐κB signaling pathway

AbstractIn this study, we aimed to investigate the effect and underlying mechanism of betulinic acid (BA) on myocardial dysfunction in septic rats. Twenty‐four male Sprague–Dawley rats were randomly allocated into four groups (n = 6 rats/group): the sham operation (Control) group, the cecal ligation and puncture (CLP) group, the BA 10 mg/kg group, and the BA 50 mg/kg group. The septic rat model was induced through cecal ligation and puncture in the CLP and BA groups, except for the Control group. Then, cardiac function parameters were assessed using echocardiography, myocardial injury markers were quantified via biochemical assays, and myocardial histopathological injuries were observed through H&E staining. Inflammatory factors in the serum were measured using ELISA assays, immunohistochemistry and qRT‐PCR were performed to determine macrophage numbers and the expression of iNOS, CD86, Arg‐1, and Mrc1 in myocardial tissue. The protein expression levels of TLR4, Myd88, and NF‐κB in myocardial tissue were assessed through western blot analysis. The results showed that BA significantly improved cardiac function, reduced myocardial injury, and attenuated inflammation in CLP rats. Specifically, BA decreased LVEDD and LVESD while increasing LVEF and LVFS. Furthermore, BA upregulated the levels of BNP, cTnT, CK‐MB, LDH, IL‐6, IL‐1β, and TNF‐α in CLP rat serum. Additionally, BA reduced macrophage infiltration, inhibited M1/M2 gene expression, and downregulated TLR4, Myd88 and NF‐κB protein expression in CLP rats myocardial tissues. In conclusion, BA can inhibit myocardial inflammation and prevent sepsis‐induced myocardial dysfunction by inhibiting TLR4/MyD88/NF‐κB signaling, thereby promoting M2 macrophage polarization in myocardial tissues.

Glycyrrhizic Acid Protects Experimental Sepsis Rats against Acute Lung Injury and Inflammation.

Background The incidence of acute lung injury/acute respiratory distress (ALI/ARDS) is high in sepsis aggravating morbidity and mortality. Glycyrrhizic acid (GA) has pharmacological activities in the treatment of inflammation and antiviral. Materials and Methods Sepsis rats were constructed by the cecal ligation and puncture (CLP) surgery. After GA (25 and 50 mg/kg) injection, the survival rate, blood oxygen, biochemical indexes, myeloperoxidase (MPO) activity, and wet/dry weight ratio of the lung were observed. The bronchoalveolar lavage fluid was collected to count the cells and measure the level of TNF-α, IL-1β, IL-10, and high mobility group box-1 protein (HMGB1). Lung tissue sections were taken to observe the levels of histopathological injury and apoptosis by HE and TUNEL staining. The levels of HMGB1, TLR4, p-38 MAPK, NF-κB, and ERK1/2 proteins were observed by immunohistochemistry and Western blot. Results GA treatment improved the survival rate, blood oxygen, ALT, AST, BUN, and Scr of CLP rats. It could advance the MPO activity, the wet/dry weight ratio, histopathological injury, apoptosis, and the IL-10 level in the lung. After GA injection, the number of total cells, neutrophils, and macrophages in the CLP rats was reduced and the levels of TNF-α, IL-1β, HMGB1, TLR4, p-38 MAPK, and ERK1/2 in the CLP rat were also repressed. Conclusions GA treatment may improve the sepsis-induced ALI/ARDS and inflammation by inhibiting HMBG1. This study provided an experimental basis for the prevention and treatment of ALI/ARDS caused by sepsis.

Galectin-3 in septic acute kidney injury: a translational study

BackgroundGalectin-3 (Gal-3) is a pleiotropic glycan-binding protein shown to be involved in sepsis and acute kidney injury (AKI). However, its role has never been elucidated in sepsis-associated AKI (S-AKI). We aimed to explore Gal-3’s role and its potential utility as a therapeutic target in S-AKI.MethodsIn 57 patients admitted to the intensive care unit (ICU) with sepsis, serum Gal-3 was examined as a predictor of ICU mortality and development of AKI. In a rat model of S-AKI induced by cecal ligation and puncture (CLP), 7-day mortality and serum Gal-3, Interleukin-6 (IL-6), and creatinine were examined at 2, 8, and 24 hours (h) post-CLP. Two experimental groups received the Gal-3 inhibitor modified citrus pectin (P-MCP) at 400 mg/kg/day and 1200 mg/kg/day, while the control group received water only (n = 18 in each group).ResultsAmong 57 patients, 27 developed AKI and 8 died in the ICU. Serum Gal-3 was an independent predictor of AKI (OR = 1.2 [95% CI 1.1–1.4], p = 0.01) and ICU mortality (OR = 1.4 [95% CI 1.1–2.2], p = 0.04) before and after controlling for age, AKI, and acute physiology and chronic health evaluation (APACHE II) score. In the CLP rat experiment, serum Gal-3 peaked earlier than IL-6. Serum Gal-3 was significantly lower in both P-MCP groups compared to control at 2 h post-CLP (400 mg: p = 0.003; 1200 mg: p = 0.002), and IL-6 was significantly lower in both P-MCP groups at all time points with a maximum difference at 24 h post-CLP (400 mg: p = 0.015; 1200 mg: p = 0.02). In the Gal-3 inhibitor groups, 7-day mortality was significantly reduced from 61% in the control group to 28% (400 mg P-MCP: p = 0.03) and 22% (1200 mg P-MCP: p = 0.001). Rates of AKI per RIFLE criteria were significantly reduced from 89% in the control group to 44% in both P-MCP groups (400 mg: p = 0.007; 1200 mg: p = 0.007).ConclusionsThis translational study demonstrates the importance of Gal-3 in the pathogenesis of S-AKI, and its potential utility as a therapeutic target.Graphic abstract

Effect of Electroacupuncture at Zusanli (ST36) on Sepsis Induced by Cecal Ligation Puncture and Its Relevance to Spleen.

Background Acupuncture at Zusanli (ST36), Quchi (LI11), and Tianshu (ST25) is commonly used in septic patients by traditional Chinese physicians. The protective effect of acupuncture at ST36 on the intestinal barrier is associated with Cholinergic Anti-Inflammatory Pathway (CAIP). However, its detailed mechanism and whether acupuncture at LI11 and ST25 have similar effects to ST36 remain unclear. Aim To explore the effects of electroacupuncture (EA) at ST36, LI11, and ST25 on septic rats and investigate the role of the spleen in the treatment of EA at ST36. Methods A septic rat model caused by cecal ligation and puncture (CLP) and a postsplenectomy (SPX) CLP rat model were established. Rats were divided into nine groups depending on different treatments. Serum levels of TNF-α, IL-10, D-lactic acidosis (D-LA), double amine oxidase (DAO), and T-lymphocyte subgroup level in intestinal lymph nodes were compared. Results EA could not improve the 2-day survival of CLP rats. For CLP rats, EA at ST36 and LI11 significantly decreased the levels of TNF-α, IL-10, DAO, and D-LA in serum and normalized intestinal T-cell immunity. For SPX CLP rats, EA at ST36 failed to reduce serum concentrations of TNF-α, IL-10, and D-LA but increased the values of CD3+CD4+/CD3+CD8+ cells and Treg/Th17 cells. Conclusions EA at ST36 and LI11, respectively, could alleviate inflammation reaction, protect the intestinal barrier, and maintain intestinal T-cell function in septic rats. Spleen participated in the protective effect of EA at ST36 in sepsis.

CD123 thioaptamer protects against sepsis via the blockade between IL-3/CD123 in a cecal ligation and puncture rat model

Sepsis is one of the most common causes of death in ICU and especially is a harmful and a life-threatened disease to pediatrics in the world. It has been demonstrated that IL-3 plays an essential role in the processing of sepsis and the inhibition of IL-3 may alleviate sepsis progress. In our previous study, we selected a novel CD123 aptamer successfully which could inhibit the interaction of CD123 and IL-3. The aim of this study is to explore the protection ability of the first thioaptamer SS30 against sepsis in a cecal ligation and puncture (CLP) rat model. Serum IL-3 level of sepsis patients was assessed by ELISA. CLP rat model was applied in all experimental groups. CD123 thioaptamer SS30 and CD123 antibody were used to block the recognition between IL-3 and CD123. Body weight, temperature, blood gas, MAP, and serum cytokines of four grouped rats were assessed. Flow cytometry was utilized to evaluate JAK2 and STAT5 proteins. After the administration of SS30 or CD123 antibody, the rats in SS30 and CD123 antibody group had lower cytokines values(lactate, TNF-α, IL-1β, and IL-6), whereas exhibited higher value of core temperature, MAP, PO2/FiO2, and ETCO2 than those in the CLP group. The expression level of phosphorylated JAK2 and STAT5 was declined and the survival rate of rats was increased. In addition, the protection ability of SS30 was better than CD123 antibody. Therefore, CD123 thioaptamer SS30 could reduce mortality by down-regulating the phosphorylated JAK2/STAT5 signaling pathway, and reduce serum cytokines which involving in sepsis development in CLP rat model.

MicroRNA-191-5p diminished sepsis-induced acute kidney injury through targeting oxidative stress responsive 1 in rat models.

There is no effective treatment for septic acute kidney injury (AKI), which is considered a major public health concern in today’s world. Here, we studied the functions of miR-191-5p in septic AKI. MiR-191-5p mimic or mimic control was injected into rats from caudal vein before cecal ligation and puncture (CLP) surgery. Part of kidney tissues was stained by Hematoxylin and Eosin (H&E) for histological examination. The levels of serum cytokines were evaluated using enzyme-linked immunosorbent assay (ELISA). For cell transfection, renal cells were isolated from the kidneys of CLP rat model injected with mimic control and miR-191-5p mimic. With TargetScan prediction, serine/threonine-protein kinase OSR1 was identified as a target of miR-191-5p. Oxidative stress responsive 1 (OXSR1) overexpression vector was transfected into renal cells. Cell viability and apoptosis rate were determined by Cell Counting Kit-8 (CCK-8) and flow cytometry, respectively. We additionally measured the phosphorylation levels of p38 and p65. We found that the injection of miR-191-5p mimic could observably inhibit renal injury scores, and inhibit inflammatory cytokine productions and apoptotic protein levels in septic rats. After being transfected with OXSR1, the apoptosis rates and expressions of B-cell lymphoma-2 (Bcl-2), down-regulated Bax and Cleaved caspase-3 (C caspase-3) indicated overexpressed OXSR1 contributed to cell apoptosis. The up-regulated protein levels of p-p38 and p-p65 may suggest the involvement of p38 MAPK/NF-κB signaling pathway in the functions of OXSR1. Our results showed that the protective effects of miR-191-5p on kidney tissues of septic rats may rely on the repression of OXSR1.

Evaluation of Gamma Irradiation Effect on the Oxidative Stress Factors in Septic Rats Treated With Iranian Plant Essential Oils

ABSTRACT Cuminum cyminum L. (CM), Zataria multiflora Boiss. (ZM) and Mentha piperita L. (MP) are traditional medicinal plants with various pharmacological properties. This study was designed to assess the role of gamma irradiation -a modern decontamination method- in hepatoprotective effects of their essential oil (E.Os) in septic rats induced by experimental cecal ligation and puncture (CLP) model. The rats were divided into 20 groups; sham-operated (SOP); CLP; CLP + CM, ZM and MP (E.Os) (100 & 200 mg/kg b.w) and CLP + gamma irradiated (10 and 25 kGy) E.Os (100 & 200 mg/kg b.w) as treatment groups. All E.Os were injected i.p immediately after sepsis induction. 24 hour after CLP, the rats were sacrificed and the liver tissue was examined considering lipid peroxiation (LP), glutathione (GSH) and myeloperoxidase (MPO) activity. The results indicated that CLP operation caused significant (P<0.05) increase in the LP and MPO levels concomitant with decreased GSH level. Administration of the E.Os (100 and 200 mg/kg b.w) extracted from non irradiated plants as well as the irradiated (10 and 25 kGy) plant E.Os could significantly (P<0.05) modulate the levels of LP, MPO and GSH. It can be concluded that all E.Os even after irradiation exposure could modulate the oxidative injury parameters related to liver damages in CLP rat model. In conclusion, the plant irradiation didn’t have any adverse effects on the hepatoprotective activities of the extracted oils.

Glutamine reduces myocardial cell apoptosis in a rat model of sepsis by promoting expression of heat shock protein 90

BackgroundMyocardial cell injury and cardiac myocyte apoptosis are associated with sepsis. Glutamine (Gln) has been reported to repair myocardial cell injury. The aim of this study was to explore the role of Gln on cardiac myocytes in a cecal ligation and puncture (CLP) model of sepsis in Wistar rats. Materials and methodsFollowing induction of sepsis in a CLP rat model, viral encoding heat shock protein 90 (Hsp90) gene and Hsp90dsDNA were designed to express and knockdown Hsp90, respectively. Rat cardiac tissues were examined histologically, and apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling staining. The expression of B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein, Hsp90, p53 upregulated modulator of apoptosis, and p53 was measured by western blotting and real-time polymerase chain reaction. Caspase-3, caspase-8, and caspase-9 were detected by enzyme-linked immunosorbent assay. ResultsRat cardiac myocyte damage induced by CLP was reduced by Gln treatment and Hsp90 overexpression, and these changes were reversed by Hsp90 knockdown. Bcl-2 expression, Bcl-2-associated X protein, p53, p53 upregulated modulator of apoptosis, caspase-8, caspase-9, and caspase-3 activities were significantly upregulated in the CLP model, which were reduced by Gln treatment and Hsp90 overexpression. ConclusionsGln reduced apoptosis of cardiac myocytes in a rat model of sepsis, by promoting Hsp90 expression. Further studies are needed to determine the possible therapeutic action of Gln in sepsis in human tissue.

Protection of resveratrol on acute kidney injury in septic rats.

The aim of the study is to investigate protective effect of resveratrol (Res) on acute kidney injury (AKI) in sepsis. Rats in sham group received sham operation; in sham + Res received sham operation and Res (3 mg/kg); in cecal ligation and puncture (CLP) established as sepsis; in CLP + Res (3 mg/kg) with sepsis and Res (3 mg/kg); and in CLP + Res (10 mg/kg) with sepsis and Res (10 mg/kg). Survival rate, serum indexes, inflammatory factors, NF-κB-P65, and SIRT1 were detected. Lipopolysaccharide (LPS) mesangial cell was with Res and SIRT1 silencing. (1) Res intervention improved survival rate of CLP rat. (2) Compared to sham, serum creatinine, blood urine nitrogen, serum cystatin C, neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, tumor necrosis factor-α, interleukin-1β, IL-6, and renal injury index increased in CLP group, while decreased in CLP + Res (3 mg/kg) and CLP + Res (10 mg/kg), significantly, as dose-dependent ( p < 0.05). (3) With Res, NF-κB-P65 and de-acetylated SIRT1 decreased, while SIRT1 and de-acetylated Nuclear factor kB-p65 9 NF-κB-P65) increased, significantly ( p < 0.05). (4) SIRT1 and de-acetylated NF-κB-P65 decreased in LPS cells, while SIRT1 increased after Res intervention, significantly ( p < 0.05). After silencing SIRT1, de-acetylated NF-κB-P65 increased, significantly ( p < 0.05). Res increases the survival rate of septic rats by inhibiting inflammatory factors to ease AKI and promotes NF-κB-P65 de-acetylation by upregulating SIRT1.

Blocking NAD+/CD38/cADPR/Ca2+ pathway in sepsis prevents organ damage

BackgroundAlthough the nicotinamide adenine dinucleotide (NAD+)/CD38/cyclic ADP ribose (cADPR)/Ca2+ signaling pathway has been shown to regulate intracellular calcium homeostasis and functions in multiple inflammatory processes, its role in sepsis remains unknown. The aim of this study was to determine whether the NAD+/CD38/cADPR/Ca2+ signaling pathway is activated during sepsis and whether an inhibitor of this pathway, 8-Br-cADPR, protects the organs from sepsis-induced damage. Materials and methodsMale Sprague–Dawley rats were subjected to cecal ligation and puncture (CLP) or sham laparotomies. NAD+, cADPR, CD38, and intracellular Ca2+ levels were measured in the hearts, livers, and kidneys of septic rats at 0, 6, 12, 24, and 48 h after CLP surgery. Rats were also divided into sham, CLP, and CLP+8-Br-cADPR groups, and the hearts, livers, and kidneys were hematoxylin–eosin-stained and assayed for malondialdehyde and superoxide dismutase activities. ResultsNAD+, cADPR, CD38, and intracellular Ca2+ levels increased in the hearts, livers, and kidneys of septic rats as early as 6–24 h after CLP surgery. Treatment with 8-Br-cADPR inhibited sepsis-induced intracellular Ca2+ mobilization, attenuated tissue injury, reduced malondialdehyde levels, and increased superoxide dismutase activity in septic rats. ConclusionsThe NAD+/CD38/cADPR/Ca2+ signaling pathway was activated during sepsis in the CLP rat model. Blocking this pathway with 8-Br-cADPR protected hearts, livers, and kidneys from sepsis-induced damage.

Matrix metalloproteinase inhibitors prevent sepsis-induced refractoriness to vasoconstrictors in the cecal ligation and puncture model in rats

Previous studies have shown that the loss of contractility in aortas from lipopolysaccharide (LPS)-treated rats is related to intracellular activation of matrix metalloproteinase (MMPs). However, the role of MMPs in the vascular refractoriness to vasoconstrictors has not been investigated in a model of polymicrobial sepsis. We evaluated the effects of the oral administration of the MMP inhibitors doxycycline or ONO-4817 in the in vitro vascular reactivity of aortic rings from rats subjected to the cecal ligation and puncture (CLP) model of sepsis. Both doxycycline and ONO-4817 did not change vascular responses in sham-operated rats, but fully prevented hyporeactivity to KCl, phenylephrine and angiotensin II in vessels from CLP rats. This protective effect was not associated with changes in hematological parameters or blood nitrate and nitrite. The refractoriness to contractile agents was accompanied by enhanced activity of MMP-2 in aorta from CLP rats, which was abrogated by MMP inhibitors. CLP-induced sepsis did not impair the levels of MMP-2 in aorta, but significantly reduced calponin-1, a regulatory protein of vascular contraction. In addition, augmented levels of TIMP-1 were found in vessels from CLP rats. All these differences were prevented by either doxycycline or ONO-4817. Our study shows, for the first time in the CLP rat model of sepsis, that the vascular refractoriness to different contractile agents induced by polymicrobial sepsis is associated with increased activity of MMP-2 and reduced amounts of calponin-1 in the aorta. These findings reinforce the importance of the enhanced activity of MMPs for vascular failure in septic shock.

The Effects of Sepsis on Osmosensory Neurons Mediating Thirst

The ability of osmosensory neurons within the hypothalamus to sense changes in blood osmolality is essential for maintaining hydromineral homeostasis. Typically, an increase in blood osmolality excites the osmosensitive neurons of the organum vasculosum of the lamina terminalis (OVLT), which then stimulate neural pathways to induce thirst sensation. Patient studies show that thirst is depressed in sepsis, a deadly disease defined by the systemic inflammatory response to a severe infection, and that this impairment may be due to a deficit in the osmoregulatory pathway. Using the rat cecal‐ligation and puncture (CLP) sepsis model, we tested the hypothesis that sepsis impairs osmotically‐induced thirst and that this is due to changes in osmosensory OVLT neuron properties. Septic rats did indeed drink significantly less under systemic hypertonic conditions (CLP 4.2 ± 0.58mL; controls 16.4 ± 1.8mL; p &lt; 0.001). Electrophysiological recordings of acute in vitro hypothalamic preparations show that septic OVLT neurons are quiescent due to their hyperpolarized state (CLP −47.9 ± 2.4mV; controls −41.0 ± 2.2mV; p = 0.02). Furthermore, they display an impaired increase in firing rate in response to hypertonicity (CLP 0.1 ± 0.05Hz; controls 0.52 ± 0.18Hz; p &lt; 0.01). These results imply that the CLP rat model mimics the human septic condition, and provide a platform to further our understanding of how central osmoregulation and osmotic thirst are perturbed at a cellular and molecular level in sepsis.

Ulinastatin is a novel candidate drug for sepsis and secondary acute lung injury, evidence from an optimized CLP rat model

Ulinastatin is a potent multivalent serine protease inhibitor, which was recently found with therapeutic potentials in treating sepsis, and the most life-threatening complication of critically ill population. However, the pharmacological features and possible mechanisms need to be further elucidated in reliable and clinical relevant sepsis models. As known, sepsis induced by surgery of cecal ligation and puncture (CLP) is widely accepted as the gold standard animal model, but the inconsistency of outcomes is the most obvious problem. In the present experiments, we reported an improved rat CLP model with much more consistent outcomes using self-made three edged puncture needles in our lab. Results from this optimized model revealed that ulinastatin improved survivals of CLP rats, attenuated proinflammatory response and prevented systemic disorder and organ dysfunction. Ulinastatin was also found to be effective in ameliorating sepsis-related ALI, a syndrome most frequent and fatal in sepsis. The molecular mechanism investigation showed that ulinastatin's protection against ALI was probably related to the down-regulation of NF-κB activity and inhibition of TNF-α, IL-6 and elastase expressions in the lung tissue. In conclusion, based on a successful establishment of optimized rat CLP model ulinastatin is proved to be an effective candidate for sepsis treatment, due to its anti-inflammation and anti-protease activities that ameliorate systemic disorders, prevent organ injuries and thus improve the survival outcomes of sepsis in animals.

Investigation of STW 5 (Iberogast®) preventive effects in experimental sepsis

Context: STW 5 (Iberogast®) is a well known herbal combination drug containing glycosides and flavonoids for which multiple pharmacological properties have been shown.Objective: In this study, attempts were made to assess whether STW 5, an aqueous ethanol solution, has a preventive effect against liver and lung pathological damage in rats after experimental induction of sepsis [cecal ligation and puncture (CLP)].Materials and methods: Experimental sepsis was induced in rats using CLP operation. The rats (n = 36) were divided into six groups (six/group): Sham-operated (SOP); CLP; CLP + STW 5 (2.5, 5 and 10 mg/kg) and CLP + indomethacin. The drugs were injected intraperitoneally immediately after sepsis induction.Results: It was found that induction of sepsis 24 h after CLP was associated with significant liver and lung damage, also remaining after STW 5 administration.Discussion and conclusion: It appears that STW 5, which has a pronounced efficacy in functional gastro-intestinal diseases, has no effect on septic liver and lung damage in the CLP rat model.

Effect of Traumeel S on Cytokine Profile in a Cecal Ligation and Puncture (CLP) Sepsis Model in Rats

Sepsis results in significant morbidity and mortality, with current treatment options limited with respect to efficacy as well as safety. The complex homeopathic remedy Traumeel S has been shown to have both anti-inflammatory and immunostimulatory effects in the in vitro setting. The objective was to explore the effects of Traumeel S in an in vivo setting, using a cecal ligation and puncture (CLP) sepsis model in rats, evaluating the effects of the medication on cytokine activity. Sepsis was induced in 30 rats using accepted CLP methodology. Following the procedure, rats were randomly allocated to receive an intraperitoneal injection of either Traumeel S (n=15) or normal saline (n=15). At 6 hours post-CLP, serum cytokines (interleukin [IL]-1β, tumor necrosis factor-α, IL-6, and IL-10) were evaluated. IL-1β levels were significantly higher in the treatment group (p=0.03) with no significant differences found between the groups with respect to the other cytokines tested. In contrast to in vitro studies, Traumeel significantly increased IL-1β levels in an in vivo model, without influencing other cytokines. IL-1β is a proinflammatory cytokine that has been shown to have a protective effect in the CLP rat model. Further research is warranted to examine this finding, as well as its clinical implications.

HETEROGENOUS AND COMPARTMENT-SPECIFIC ACTIVATION OF NONLYMPHOCYTIC, MONONUCLEAR CELLS IN INTRA-ABDOMINAL SEPSIS

Although sepsis is associated with increased production of cellular pro- and anti-inflammatory mediators by monocyte/macrophages, the compartmentalization and nature of such activation has not been clearly defined. The authors examined the activation of nonlymphocytic mononuclear cells in different compartments in the cecal ligation and puncture (CLP) model of septic peritonitis. Control and CLP rat mononuclear cells from the peritoneal cavity, bronchoalveolar, as well as the lung vascular compartment were isolated 24 and 48 hours post surgery and release of nitric oxide (NO), interleukin(IL)-12, and monocyte chemoattractant protein-1 (MCP-1) was measured from culture media. Peritoneal macrophages (PMs) from CLP rats increased release of all three mediators compared to controls. Cells from the lung vascular compartment after CLP increased release of NO, but MCP-1 release was unchanged. Levels of IL-12 were not detectable. Similarly, bronchoalveolar macrophages (BMs) of CLP rats had increased release of NO, whereas IL-12 was not detectable. Release of MCP-1 increased 48 hours after CLP. Almost all PMs and BMs possessed innate phagocytic ability that was not altered during sepsis. The percentage of cells in the lung vascular compartment that had phagocytic ability, increased 48 hours post CLP, versus controls. The authors also evaluated lung injury at 24 hours after surgery by measurement of bronchoalveolar lavage protein and LDH activity. There was an increase in both these parameters 24 hours after CLP as compared to controls. Thus, there was heterogenous and compartment-specific activation of mononuclear cells in sepsis. There was nonspecific inflammatory activation in the primary site of injury. In a remote organ (lung), the authors show for the first time that there was selective activation of NO without increased release of the proinflammatory cytokine, IL-12. Phagocytic activity was maintained in the bronchoalveolar compartment whereas in the lung vascular compartment, the percentage of phagocytic cells increased.