Intestinal Lymph-Borne Factors Induce Lung Release of Inflammatory Mediators and Expression of Adhesion Molecules After an Intestinal Ischemic Insult (original) (raw)
Related papers
The American Journal of Surgery, 2002
We tested the hypothesis that lung injury after intestinal ischemia-reperfusion (IR) requires the activation of CD11/CD18 glycoprotein complex and its ligand, intracellular adhesion molecule-1 (ICAM-1), on pulmonary endothelial surface. Methods: Rats were assigned to one of six groups including sham operation, intestinal IR (60/120 min) and IR plus treatment with one of the following monoclonal antibodies against CD11a, CD11b, CD18, and ICAM-1. Pulmonary microvascular permeability, neutrophil accumulation, and expression of adhesion molecules were evaluated. Results: Intestinal IR resulted in lung injury characterized by a marked increase in microvascular permeability, neutrophil accumulation and upregulated expression of leukocyte integrins and ICAM-1. The increase in pulmonary microvascular permability and neutrophil accumulation elicited by intestinal reperfusion was effectively prevented by administration of blocking antibodies against ICAM-1, CD11, and CD18.
Lung Neutrophil Retention and Injury After Intestinal Ischemia/Reperfusion
Microcirculation, 1997
Objective: To define the mechanisms responsible for the lung leukosequestration and injury elicited by intestinal ischemidreperfusion (I/R). Methods: The effect of 120 minutes of superior mesenteric artery occlusion and 90 minutes of reperfusion on neutrophil deformability, lung neutrophil retention, and pulmonary microvascular permeability was determined. Results: Compared with control surgery, intestinal I/R resulted in a significant increase in neutrophil stiffness (mean yield pressure [P?ield]. 1.533 * 0.0?5 and 2.302 * 0.288 cm H,O, respectively) and lung neutrophil content (6.3 * 1.4 and 31.5 * 6.4 U/g wet weight, respectively). These changes were not affected by inhibition of neutrophd adherence before gut reperfusion. However, the increased lung microvascular permeability elicited by gut I/R (0.111 * 0.020 [control surgery] and 0.255 0.041 [VR] rnL/min/cm H20/100 g lung tissue) was sigdicantly attenuated by adrmnistration of antibodies directed against neutrophil or endothelial determinants of leukocyte adhesion. Conclusions: The results of t h~s study suggest that intestinal I/R is a potent inflammatory stimulus that elicits an increase in neutrophil stiffness and lung neutroplvl retention independent of neutrophil-endothelial cell adhesion. In contrast: the increased lung microvascular permeability elicited by gut I/R is attenuated by strategies that interfere with neutrophil-endothelial cell adhesion.
Gut Ischemia/Reperfusion Induced Acute Lung Injury is an Alveolar Macrophage Dependent Event
The Journal of Trauma: Injury, Infection, and Critical Care, 2008
Background: Although the role of the lung alveolar macrophage (AM) as a mediator of acute lung injury (ALI) after lung ischemia/reperfusion (I/R) has been suggested by animal experiments, it has not been determined whether AMs mediate ALI after intestinal I/R. The objective of this study was to determine the effect of AM elimination on ALI after intestinal I/R in rats. Methods: Male Wistar rats (n ؍ 90) were randomly divided into three groups: the clodronate-liposomes (CLOD-LIP) group received intratracheal treatment with CLOD-LIP; the liposomes (LIP) group received intratracheal treatment with LIP; and the nontreated (UN-TREAT) group received no treatment. Twenty-four hours later each group was randomly divided into three subgroups: the intestinal I/R subgroup was subjected to 45-minute intestinal ischemia and 2-hour reperfusion; the laparotomy (LAP) subgroup was subjected to LAP and sham procedures; the control (CTR) subgroup received no treatment. At the end of reperfusion, ALI was quantitated in all the animals by the Evans blue dye (EBD) method. Results: ALI values are expressed as EBD lung leakage (g EBD/g dry lung weight). EBD lung leakage values in the CLOD-LIP group were 32.59 ؎ 12.74 for I/R, 27.74 ؎ 7.99 for LAP, and 33.52 ؎ 10.17 for CTR. In the LIP group, lung leakage values were 58.02 ؎ 18.04 for I/R, 31.90 ؎ 8.72 for LAP, and 27.17 ؎ 11.48 for CTR. In the UNTREAT group, lung leakage values were 55.60 ؎ 10.96 for I/R, 35.99 ؎ 6.89 for LAP, and 30.83 ؎ 8.41 for CTR. Within each group, LAP values did not differ from CTR values. However, in the LIP and UNTREAT groups, values for both the LAP and CTR subgroups were lower than values for the I/R subgroup (p < 0.001). The CLOD-LIP I/R subgroup value was less (p < 0.001) than the I/R subgroup values in the LIP and UNTREAT groups. These results indicated that I/R provokes ALI that can be prevented by CLOD-LIP treatment, and further suggested that AMs are essential for ALI occurrence induced by intestinal I/R in rats.
Shock, 2010
Intestinal ischemia-reperfusion (I/R) injury may cause acute systemic and lung inflammation. Here, we revisited the role of TNF-! in an intestinal I/R model in mice, showing that this cytokine is not required for the local and remote inflammatory response upon intestinal I/R injury using neutralizing TNF-! antibodies and TNF ligandYdeficient mice. We demonstrate increased neutrophil recruitment in the lung as assessed by myeloperoxidase activity and augmented IL-6, granulocyte colony-stimulating factor, and KC AQ2 levels, whereas TNF-! levels in serum were not increased and only minimally elevated in intestine and lung upon intestinal I/R injury. Importantly, TNF-! antibody neutralization neither diminished neutrophil recruitment nor any of the cytokines and chemokines evaluated. In addition, the inflammatory response was not abrogated in TNF and TNF receptors 1 and 2Ydeficient mice. However, in view of the damage on the intestinal barrier upon intestinal I/R with systemic bacterial translocation, we asked whether Toll-like receptor (TLR) activation is driving the inflammatory response. In fact, the inflammatory lung response is dramatically reduced in TLR2/ 4Ydeficient mice, confirming an important role of TLR receptor signaling causing the inflammatory lung response. In conclusion, endogenous TNF-! is not or minimally elevated and plays no role as a mediator for the inflammatory response upon ischemic tissue injury. By contrast, TLR2/4 signaling induces an orchestrated cytokine/chemokine response leading to local and remote pulmonary inflammation, and therefore disruption of TLR signaling may represent an alternative therapeutic target.
Shock, 2010
Today, there is no continuous monitoring of the bronchial epithelial lining fluid. This study used microdialysis as a method of continuous monitoring of early lung cytokine response secondary to intestinal ischemia-reperfusion in pigs. The authors aimed to examine bronchial microdialysis for continuous monitoring of IL-1", TNF-!, IL-8, and fluorescein isothiocyanate Dextran 4,000 Da (FD-4). The superior mesenteric artery was cross-clamped for 120 min followed by 240 min of reperfusion (ischemia group, n = 8). Four sham-operated pigs served as controls. The pigs were anesthetized and normoventilated (peak inspiratory pressure, G20 cm H 2 O; positive end-expiratory pressure, 7 cm H 2 O). Samples from bronchial and luminal intestinal and arterial microdialysis catheters (flow-rate of 1 2L/min) were collected during reperfusion in 60-min fractions. Samples were analyzed for TNF-!, IL-1", IL-8, and FD-4. Data are presented as median (interquartile range). A lung biopsy was collected at the end of the experiment. During reperfusion, there was an increase in bronchial concentrations of both IL-8 (3.70 [1.47Y8.93] ng/mL per h vs. controls, 0.61 [0.47Y0.91] ng/mL per h; P G 0.001) and IL-1" (0.32 [0.05Y0.56] ng/mL per h vs. controls, 0.07 [0.04Y0.10] ng/mL per h; P = 0.008). In the intestinal lumen, IL-8 was increased in the ischemia group (6.33 [3.13Y9.23] ng/mL per h vs. controls, 0.89 [0.21Y1.86] ng/mL per h; P G 0.001). The FD-4 did not differ between groups. Pulmonary vascular resistance and pulmonary shunt increased versus controls. During reperfusion, PaO 2 /FiO 2 ratio decreased in the ischemia group. Histology was normal in both groups. Bronchial microdialysis detects altered levels of cytokines in the epithelial lining fluid and can be used for continuous monitoring of the immediate local lung cytokine response secondary to intestinal ischemia-reperfusion.
Intestinal Ischemia/Reperfusion Induces Bronchial Hyperreactivity and Increases Serum TNF-Α in Rats
Clinics, 2006
INTRODUCTION: Intestinal or hepatic ischemia/reperfusion induces acute lung injury in animal models of multiple organ failure. Tumor necrosis factor (TNF)-α is involved in the underlying inflammatory mechanism of acute respiratory distress syndrome. Although the inflammatory cascade leading to acute respiratory distress syndrome has been extensively investigated, the mechanical components of acute respiratory distress syndrome are not fully understood. Our hypothesis is that splanchnic ischemia/reperfusion increases airway reactivity and serum TNF-α levels. OBJECTIVE: To assess bronchial smooth muscle reactivity under methacholine stimulation, and to measure serum TNF-α levels following intestinal and/or hepatic ischemia/reperfusion in rats. METHOD: Rats were subjected to 45 minutes of intestinal ischemia, or 20 minutes of hepatic ischemia, or to both (double ischemia), or sham procedures (control), followed by 120 minutes of reperfusion. The animals were then sacrificed, and the bronchial response to increasing methacholine molar concentrations (10-7 to 3 x 10-4) was evaluated in an ex-vivo bronchial muscle preparation. Serum TNF-α was determined by the L929-cell bioassay. RESULTS: Bronchial response (g/100 mg tissue) showed increased reactivity to increasing methacholine concentrations in the intestinal ischemia and double ischemia groups, but not in the hepatic ischemia group. Similarly, serum TNF-α (pg/mL) concentration was increased in the intestinal ischemia and double ischemia groups, but not in the hepatic ischemia group. CONCLUSION: Intestinal ischemia, either isolated or associated with hepatic ischemia, increased bronchial smooth muscle reactivity, suggesting a possible role for bronchial constriction in respiratory dysfunction following splanchnic ischemia/reperfusion. This increase occurred in concomitance with serum TNF-α increase, but whether the increase in TNF-α caused this bronchial contractility remains to be determined.
Gut Ischemia-Reperfusion Primes the Neutrophil, the Lung, and the Host
Nihon Kyukyu Igakukai Zasshi, 1996
The gut and the neutrophil have been emphasized to play mechanistic roles in the development of adult respiratory distress syndrome and multiple organ failure (MOF). While a massive single insult (one-hit model) can precipitate early MOF, the more classic presentation is multiple sequential insults (two-hit model) in which the inflammatory system is primed to respond to a secondary activating stimulus. We hypothesized that gut ischemia/reperfusion (I/R) primes the systemic inflammatory cascade and a subsequent activating stimulus results in distant organ injury. Adult male Sprague-Dawley rats underwent 45min of superior mesenteric artery occlusion and ensuing reperfusion (gut I/R) as the first insult. A second insult, low dose endotoxin (2.5mg/kg), was given at 6hr reperfusion and the effects on pulmonary capillary permeability (assessed by 125-albumin leak) and mortality were determined. Forty-five min of laparotomy (LAP) was the control for gut Ischemia while saline injection 6hr later was the control for endotoxin. The animals were allocated into 4 groups: i) LAP+Saline, ii) I/R+Saline, iii) LAP+Endotoxin, and iv) I/ R+Endotoxin. Only the combined insult, I/R+Endotoxin, increased 125I-albumin lung leakage at 18hr reperfusion and the mortality rate of this group was 39% which was significantly higher than those of LAP+Saline (0%), I/R+Saline (0%) and LAP+Endotoxin (4%). In the next study, the effects of the priming event (gut I/R; 45min/6hr) on the lung and neutrophils were investigated. Neutrophil depleted animals were obtained by pretreatment with vinblastine (0.75mg/kg, iv, 3 days prior). Lung leakage was again measured by the 125I-albumin leak while pulmonary neutrophil sequestration was quantitated by myeloperoxidase assay. Circulating neutrophil priming was reflected by the difference in superoxide production with and without the activating stimulus, Nformyl-methionyl-leucyl-phenylalanine. We observed that, a) 45min of gut ischemia provoked transient mild lung leakage at 6hr reperfusion which had normalized by 18hr, b) this transient lung leakage was abrogated by neutrophil depletion, c) both gut I/R and sham-laparotomy increased lung neutrophil accumulation, and d) only gut I/R markedly primed circulating neutrophils. These findings indicate that a relatively brief period of gut I/R primes the neutrophil, the lung and the host such that low dose endotoxin exposure activates inflammatory mechanisms, resulting in advanced pulmonary failure and mortality.
Mechanisms of acute inflammatory lung injury induced by abdominal sepsis
International Immunology, 1999
Mechanisms of inflammatory lung injury caused by abdominal sepsis were investigated using the colon ascendens stent peritonitis (CASP) model that closely mimics the human disease. In the CASP model, a continuous leakage of intraluminal bacteria into the peritoneal cavity is induced by implantation of a stent in the ascending colon, generating a septic focus. In contrast to the cecal ligation and puncture model of peritonitis, survival of mice following CASP surgery is dependent on IFN-γ, but independent of tumor necrosis factor (TNF). Here we show that the systemic inflammation induced by CASP surgery results in a rapid and profound increase of lung vascular permeability that was associated with the activation and recruitment of neutrophils to the lung. Activation of circulating granulocytes was characterized by increased production of serine proteinases and reactive oxygen metabolites, as well as elevated expression of cell surface Mac-1. Expression of MIP-2, KC, MIP-1α and E-selectin mRNA in lung was strongly increased within 3 h following CASP surgery, whereas up-regulation of IP-10, MCP-1 and P-selectin was delayed. In contrast, induction of RANTES, LIX, ICAM-1 and VCAM-1 mRNA was weak or not detectable after CASP surgery. Importantly, recruitment of leukocytes to the lung was normal in lipopolysaccharideresistant mice, and was not affected by antibody neutralization of TNF or the chemokines MIP-2 and KC.
Shock, 2002
Trauma/hemorrhagic shock (T/HS) is associated with significant lung injury, which is mainly due to an inflammatory process, resulting from the local activation and subsequent interaction of endothelial cells and leukocytes. Adhesion molecules expressed by both cell types play a crucial role in the process of neutrophil-mediated endothelial cell injury. We have previously shown that mesenteric lymph duct ligation prevents T/HS-induced lung leukocyte infiltration and endothelial injury, suggesting that inflammatory factors originating from the gut and carried in the lymph are responsible for the lung injury observed following T/HS. Based on these observations, we hypothesized that inflammatory substances in T/HS lymph trigger lung injury by a mechanism involving the upregulation of adhesion molecules. To test this hypothesis, we examined whether T/HS mesenteric lymph induces the expression of E-selectin, P-selectin, and intracellular adhesion molecule-1 (ICAM-1) in human umbilical vein endothelial cells (HUVECs). Furthermore, because the cytokine IL-6 is an important component of the endothelial inflammatory process, we investigated how T/HS lymph affects the production of IL-6 by HUVECs. Mesenteric lymph from T/HS rats increased both E-and P-selectin, as well as ICAM-1 expression on HUVECS, as compared to trauma/sham shock (T/SS) lymph or medium only groups. However, T/HS lymph failed to induce the shedding of E-selectin. In HUVECs treated with T/HS lymph, IL-6 concentrations were higher than HUVECs treated with T/SS lymph. These findings suggest that mesenteric lymph produced after hemorrhagic shock potentiates lung injury by the upregulation of endothelial cell adhesion molecule expression and IL-6 production.