Pancreaticoduodenal Artery Aneurysm Complicated by Median Arcuate Ligament Syndrome.

PURPOSE: To highlight median arcuate ligament syndrome as a potential cause for celiac artery stenosis and pancreaticoduodenal artery aneurysm, and describe treatment options in this setting. CASE REPORT: A 63-year-old male presented with a pancreaticoduodenal artery aneurysm and concomitant celiac artery stenosis that was treated with celiac artery stenting and aneurysm coiling. He subsequently developed stent fracture and celiac artery occlusion secondary to previously unrecognized median arcuate ligament syndrome causing reperfusion of the aneurysm. This was treated with open median arcuate ligament release and aorta to common hepatic artery bypass with good clinical result and stable 20-month surveillance imaging. CONCLUSION: It is critical to recognize median arcuate ligament syndrome as a cause of celiac artery stenosis in the setting of pancreaticoduodenal artery aneurysm given the high risk of failure of endovascular stenting. Open aorto-hepatic artery bypass and endovascular aneurysm coiling should be the preferred approach in these patients.

Portal vein thrombosis after second Pfizer/BioNTech coronavirus disease 2019 vaccine.

We have reviewed a case of portomesenteric venous thrombosis that occurred shortly after the administration of the second Pfizer/BioNTech coronavirus disease 2019 (COVID-19) vaccine and discussed the literature surrounding the subject. Our report was generated after reviewing the patient's medical records and clinical images with his written informed consent. The literature review was conducted using PubMed and Google Scholar. Portomesenteric venous thrombosis after the Pfizer/BioNTech COVID-19 vaccine has previously been reported, although infrequently. We did not find enough information, given the paucity of the reported data, to assert a causative relationship between the Pfizer/BioNTech COVID-19 vaccine and the occurrence of portomesenteric thrombosis.

Aortoiliac thrombosis in COVID-19 patients: A case series.

Severe acute respiratory syndrome coronavirus 2 infection has been associated with a prothrombotic state. Reports of arterial and venous thrombosis have emerged. Here, we report three cases of aortoiliac thrombosis presenting as mesenteric and lower extremity ischemia in coronavirus disease 2019 patients with no identifiable proximal embolic source or history of prothrombotic condition.

Outcomes of Carotid Revascularization in the Treatment of Restenosis After Prior Carotid Endarterectomy.

Background and Purpose: Restenosis after carotid endarterectomy (CEA) is associated with an increased risk of ipsilateral stroke. The optimal procedural modality for this indication has yet to be determined. Here, we evaluate the in-hospital outcomes of transcarotid artery revascularization (TCAR), redo-CEA, and transfemoral carotid artery stenting (TFCAS) in a large contemporary cohort of patients who underwent treatment for restenosis after CEA. Methods: We performed a retrospective analysis of all patients in the vascular quality initiative database who underwent TCAR, redo-CEA, or TFCAS after ipsilateral CEA between September 2016 and April 2020. Patients with prior ipsilateral CAS were excluded from this analysis. In-hospital outcomes following TCAR versus CEA and TCAR versus TFCAS were evaluated using multivariate logistic regression analysis. Results: A total of 4425 patients were available for this analysis. There were 963 (21.8%) redo-CEA, 1786 (40.4%) TFCAS, and 1676 (37.9%) TCAR. TCAR was associated with lower odds of in-hospital stroke/death (odds ratio [OR], 0.41 [95% CI, 0.24­0.70], P=0.021), stroke (OR, 0.46 [95% CI, 0.23­0.93], P=0.03), myocardial infarction (MI; OR, 0.32 [95% CI, 0.14­0.73], P=0.007), stroke/transient ischemic attack (OR, 0.42 [95% CI, 0.24­0.74], P=0.002), and stroke/death/MI (OR, 0.41 [95% CI, 0.24­0.70], P=0.001) when compared with redo-CEA. There was no significant difference in the odds of death between the 2 groups (OR, 0.99 [95% CI, 0.28­3.5], P=0.995). TCAR was also associated with lower odds of stroke/transient ischemic attack (OR, 0.37 [95% CI, 0.18­0.74], P=0.005) when compared with TFCAS. There was no significant difference in the odds of stroke, death, MI, stroke/death, or stroke/death/MI between TCAR and TFCAS. Conclusions: TCAR was associated with significantly lower odds of in-hospital stroke, MI, stroke/transient ischemic attack, stroke/death, and stroke/death/MI when compared with redo-CEA and lower odds of in-hospital stroke/transient ischemic attack when compared with TFCAS. Additional long-term studies are warranted to establish the role of TCAR for the treatment of restenosis after CEA.

Tortuous ulnar artery presenting as left distal forearm mass.

Knowledge of anatomic variation in vasculature is critical to safe medical intervention as conduits vary in morphology, architecture, and course. Tortuosity is a common anatomic variant in certain arterial beds; however, its prevalence in ulnar arteries is not well documented in the literature. Here we report two cases of tortuous ulnar arteries in patients being evaluated for upper extremity hemodialysis access.

Right carotid-cutaneous fistula and right carotid pseudoaneurysm formation secondary to a chronically infected polyethylene terephthalate patch.

Carotid endarterectomy (CEA) remains the treatment for significant carotid stenosis and stroke prevention. Approximately 100,000 CEAs are performed in the United States every year. Randomized trials have demonstrated an advantage of patch carotid angioplasty over primary closure. Complications from patches include thrombosis, transient ischemic attack, stroke, restenosis, pseudoaneurysm (PA), and infection. PA after CEA is rare, with a reported average of 0.37% of cases. We describe an unusual case of PA after polyethylene terephthalate (PTFE) patching for CEA. An 88-year-old female with Alzheimer's disease living in a nursing facility with a history of skin cancer on her right chest developed a new area of intermittent brisk bleeding on her right neck which was initially believed to be related to her skin cancer. She had a remote history of right CEA with a PTFE patch approximately a decade ago. A computed tomography angiograph-head-and-neck with showed a partially thrombosed PA in the region of her right common carotid artery bifurcation with a tract containing gas and fluid extending to the skin surface suspicious for a partially thrombosed, leaking PA. She was taken urgently to the operating room on broad-spectrum antibiotics where we performed a right neck exploration, ligation of a bleeding carotid PA by ligation of the right common, internal, and external carotid arteries, explantation of a chronically infected polyethylene terephthalate patch, and closure with a sternocleidomastoid advanced flap with multilayered closure. She was discharged to her nursing facility with 6 weeks of ceftriaxone intravenous (IV) and metronidazole IV through a peripherally inserted central catheter (PICC) line with no neurological sequelae.

Mesenteric vein thrombosis can be safely treated with anticoagulation but is associated with significant sequelae of portal hypertension.

BACKGROUND: Mesenteric venous thrombosis (MVT) is a relatively uncommon but potentially lethal condition associated with bowel ischemia and infarction. The natural history and long-term outcomes are poorly understood and under-reported. METHODS: A single-institution retrospective review of noncirrhotic patients diagnosed with MVT from 1999 to 2015 was performed using International Classification of Diseases, Ninth Revision and radiology codes. Patients were excluded if no radiographic imaging was available for review. Eighty patients were identified for analysis. Demographic, clinical, and radiographic data on presentation and at long-term follow-up were collected. Long-term sequelae of portal venous hypertension were defined as esophageal varices, portal vein cavernous transformation, splenomegaly, or hepatic atrophy, as seen on follow-up imaging. RESULTS: There were 80 patients (57.5% male; mean age, 57.9 ± 15.6 years) identified; 83.3% were symptomatic, and 80% presented with abdominal pain. Median follow-up was 480 days (range, 1-6183 days). Follow-up radiographic and clinical data were available for 50 patients (62.5%). The underlying causes of MVT included cancer (41.5%), an inflammatory process (25.9%), the postoperative state (20.7%), and idiopathic cases (18.8%). Pancreatic cancer was the most common associated malignant neoplasm (53%), followed by colon cancer (15%). Twenty patients (26%) had prior or concurrent lower extremity deep venous thromboses. Most patients (68.4%) were treated with anticoagulation; the rest were treated expectantly. Ten (12.5%) had bleeding complications related to anticoagulation, including one death from intracranial hemorrhage. Four patients underwent intervention (three pharmacomechanical thrombolysis and one thrombectomy). One patient died of intestinal ischemia. Two patients had recurrent MVT, both on discontinuing anticoagulation. Long-term imaging sequelae of portal hypertension were noted in 25 of 50 patients (50%) who had follow-up imaging available. Patients with long-term sequelae had lower recanalization rates (36.8% vs 65%; P = .079) and significantly higher rates of complete as opposed to partial thrombosis at the initial event (73% vs 43.3%; P < .005). Long-term sequelae were unrelated to the initial cause or treatment with anticoagulation (P = NS). CONCLUSIONS: Most cases of MVT are associated with malignant disease or an inflammatory process, such as pancreatitis. A diagnosis of malignant disease in the setting of MVT has poor prognosis, with a 5-year survival of only 25%. MVT can be effectively treated with anticoagulation in the majority of cases. Operative or endovascular intervention is rarely needed but important to consider in patients with signs of severe ischemia or impending bowel infarction. There is a significant incidence of radiographically noted long-term sequelae from MVT related to portal venous hypertension, especially in cases of initial complete thrombosis of the mesenteric vein.

Neurovascular compromise due to true brachial artery aneurysm at the site of a previously ligated arteriovenous fistula: Case report and review of literature.

True arterial aneurysms of the upper extremity are rare. The case described is that of a 48-year-old man presenting with median neuropathy and distal vascular compromise 4 years after ligation of a brachiocephalic arteriovenous fistula. We describe our approach and present a review of the relevant literature.

Endovascular treatment of acute renal failure secondary to caval thrombosis and suprarenal filter migration.

Although inferior vena cava filter placement is a safe and effective method of reducing the risk of pulmonary embolism, devastating complications can result from thrombosis and migration. Here we present a case of acute renal failure as a result of suprarenal inferior vena cava filter migration and caval thrombosis. We discuss a novel endovascular approach for its management by mechanical aspirational thrombectomy.

Intraluminal nonbacterial intestinal components control gut and lung injury after trauma hemorrhagic shock.

OBJECTIVE: To test whether the mucus layer, luminal digestive enzymes, and intestinal mast cells are critical components in the pathogenesis of trauma shock-induced gut and lung injury. BACKGROUND: Gut origin sepsis studies have highlighted the importance of the systemic component (ischemia-reperfusion) of gut injury, whereas the intraluminal component is less well studied. METHODS: In rats subjected to trauma hemorrhagic shock (T/HS) or sham shock, the role of pancreatic enzymes in gut injury was tested by diversion of pancreatic enzymes via pancreatic duct exteriorization whereas the role of the mucus layer was tested via the enteral administration of a mucus surrogate. In addition, the role of mast cells was assessed by measuring mast cell activation and the ability of pharmacologic inhibition of mast cells to abrogate gut and lung injury. Gut and mucus injury was characterized functionally, morphologically, and chemically. RESULTS: Pancreatic duct exteriorization abrogated T/HS-induced gut barrier loss and limited chemical mucus changes. The mucus surrogate prevented T/HS-induced gut and lung injury. Finally, pancreatic enzyme-induced gut and lung injury seems to involve mast cell activation because T/HS activates mast cells and pharmacologic inhibition of intestinal mast cells prevented T/HS-induced gut and lung injury. CONCLUSIONS: These results indicate that gut and gut-induced lung injury after T/HS involves a complex process consisting of intraluminal digestive enzymes, the unstirred mucus layer, and a systemic ischemic-reperfusion injury. This suggests the possibility of intraluminal therapeutic strategies.

Oxidative modification of the intestinal mucus layer is a critical but unrecognized component of trauma hemorrhagic shock-induced gut barrier failure.

Recent studies demonstrate that mechanisms underlying gut barrier failure include systemic processes and less studied luminal processes. We thus tested the hypothesis that mucus layer oxidation is a component of trauma/hemorrhagic shock-induced gut injury and dysfunction. Male Sprague-Dawley rats underwent trauma/hemorrhagic shock. Controls underwent trauma only. Mucus from the terminal 30 cm of the ileum was collected, processed, and analyzed for reactive nitrogen intermediates (RNI)-mediated damage, reactive oxygen species (ROS)-induced damage, and total antioxidant capacity. The distal ileum was stained to quantify the mucus layer; gut permeability was assessed physiologically. A time course study was conducted to determine the temporal sequence of mucus layer damage. The role of free radical-mediated damage to the gut barrier was investigated by the effect of the free radical scavenger dimethyl sulfoxide on trauma/hemorrhagic shock-induced changes on the mucus and on gut permeability. Trauma/hemorrhagic shock increased intestinal permeability, which was associated with evidence of loss of the unstirred mucus layer. These changes correlated with increased ROS- and RNI-mediated mucus damage and loss of mucus total antioxidant capacity. Based on the time course study, ROS-mediated mucus damage and loss of total antioxidant capacity were present immediately following shock, whereas RNI-mediated damage was delayed for 3 h. Dimethyl sulfoxide ameliorated gut barrier loss, ROS-mediated changes to the mucus layer, and loss of total antioxidant capacity. There was no change in RNI-induced changes to the mucus layer. These results support the hypothesis that trauma/hemorrhagic shock leads to mucus damage and gut dysfunction through the generation of free radical species.

Role of lipase-generated free fatty acids in converting mesenteric lymph from a noncytotoxic to a cytotoxic fluid.

Recent studies have shown that mesenteric lymph plays a very important role in the development of multiple-organ dysfunction syndrome under critical conditions. Great efforts have been made to identify the biologically active molecules in the lymph. We used a trauma-hemorrhagic shock (T/HS) model and the superior mesenteric artery occlusion (SMAO) model, representing a global and a localized intestinal ischemia-reperfusion insult, respectively, to investigate the role of free fatty acids (FFAs) in the cytotoxicity of mesenteric lymph in rats. Lymph was collected before, during, and after (post) shock or SMAO. The post-T/HS and SMAO lymph, but not the sham lymph, manifested cytotoxicity for human umbilical vein endothelial cells (HUVECs). HUVEC cytotoxicity was associated with increased FFAs, especially the FFA-to-protein ratio. Addition of albumin, especially delipidated albumin, reduced this cytotoxicity. Lipase treatment of trauma-sham shock (T/SS) lymph converted it from a noncytotoxic to a cytotoxic fluid, and its toxicity correlated with the FFA-to-protein ratio in a fashion similar to that of the T/HS lymph, further suggesting that FFAs were the key components leading to HUVEC cytotoxicity. Analysis of lymph by gas chromatography revealed that the main FFAs in the post-T/HS or lipase-treated T/SS lymph were palmitic, stearic, oleic, and linoleic acids. When added to the cell culture at levels comparable to those in T/HS lymph, all these FFAs were cytotoxic, with linoleic acid being the most potent. In conclusion, this study suggests that lipase-generated FFAs are the key components resulting in the cytotoxicity of T/HS and SMAO mesenteric lymph.

Activation of toll-like receptor 4 is necessary for trauma hemorrhagic shock-induced gut injury and polymorphonuclear neutrophil priming.

Interactions of toll-like receptors (TLRs) with nonmicrobial factors play a major role in the pathogenesis of early trauma-hemorrhagic shock (T/HS)-induced organ injury and inflammation. Thus, we tested the hypothesis that TLR4 mutant (TLR4 mut) mice would be more resistant to T/HS-induced gut injury and polymorphonuclear neutrophil (PMN) priming than their wild-type littermates and found that both were significantly reduced in the TLR4 mut mice. In addition, the in vivo and ex vivo PMN priming effect of T/HS intestinal lymph observed in the wild-type mice was abrogated in TLR4 mut mice as well the TRIF mut-deficient mice and partially attenuated in Myd88 mice, suggesting that TRIF activation played a more predominant role than MyD88 in T/HS lymph-induced PMN priming. Polymorphonuclear neutrophil depletion studies showed that T/HS lymph-induced acute lung injury was PMN dependent, because lung injury was totally abrogated in PMN-depleted animals. Because the lymph samples were sterile and devoid of endotoxin or bacterial DNA, we investigated whether the effects of T/HS lymph was related to endogenous nonmicrobial TLR4 ligands. High-mobility group box 1 protein 1, heat shock protein 70, heat shock protein 27, and hyaluronic acid all have been implicated in ischemia-reperfusion-induced tissue injury. None of these "danger" proteins appeared to be involved, because their levels were similar between the sham and shock lymph samples. In conclusion, TLR4 activation is important in T/HS-induced gut injury and in T/HS lymph-induced PMN priming and lung injury. However, the T/HS-associated effects of TLR4 on gut barrier dysfunction can be uncoupled from the T/HS lymph-associated effects of TLR4 on PMN priming.

Testosterone depletion or blockade in male rats protects against trauma hemorrhagic shock-induced distant organ injury by limiting gut injury and subsequent production of biologically active mesenteric lymph.

BACKGROUND: We tested the hypothesis that testosterone depletion or blockade in male rats protects against trauma hemorrhagic shock-induced distant organ injury by limiting gut injury and subsequent production of biologically active mesenteric lymph. METHODS: Male, castrated male, or flutamide-treated rats (25 mg/kg subcutaneously after resuscitation) were subjected to a laparotomy (trauma), mesenteric lymph duct cannulation, and 90 minutes of shock (35 mm Hg) or trauma sham-shock. Mesenteric lymph was collected preshock, during shock, and postshock. Gut injury was determined at 6 hours postshock using ex vivo ileal permeability with fluorescein dextran. Postshock mesenteric lymph was assayed for biological activity in vivo by injection into mice and measuring lung permeability, neutrophil activation, and red blood cell deformability. In vitro neutrophil priming capacity of the lymph was also tested. RESULTS: Castrated and flutamide-treated male rats were significantly protected against trauma hemorrhagic shock (T/HS)-induced gut injury when compared with hormonally intact males. Postshock mesenteric lymph from male rats had a higher capacity to induce lung injury, Neutrophil (PMN) activation, and loss of red blood cell deformability when injected into naïve mice when compared with castrated and flutamide-treated males. The increase in gut injury after T/HS in males directly correlated with the in vitro biological activity of mesenteric lymph to prime neutrophils for an increased respiratory burst. CONCLUSIONS: After T/HS, gut protective effects can be observed in males after testosterone blockade or depletion. This reduced gut injury contributes to decreased biological activity of mesenteric lymph leading to attenuated systemic inflammation and distant organ injury.

Trauma hemorrhagic shock-induced lung injury involves a gut-lymph-induced TLR4 pathway in mice.

BACKGROUND: Injurious non-microbial factors released from the stressed gut during shocked states contribute to the development of acute lung injury (ALI) and multiple organ dysfunction syndrome (MODS). Since Toll-like receptors (TLR) act as sensors of tissue injury as well as microbial invasion and TLR4 signaling occurs in both sepsis and noninfectious models of ischemia/reperfusion (I/R) injury, we hypothesized that factors in the intestinal mesenteric lymph after trauma hemorrhagic shock (T/HS) mediate gut-induced lung injury via TLR4 activation. METHODS/PRINCIPAL FINDINGS: The concept that factors in T/HS lymph exiting the gut recreates ALI is evidenced by our findings that the infusion of porcine lymph, collected from animals subjected to global T/HS injury, into naïve wildtype (WT) mice induced lung injury. Using C3H/HeJ mice that harbor a TLR4 mutation, we found that TLR4 activation was necessary for the development of T/HS porcine lymph-induced lung injury as determined by Evan's blue dye (EBD) lung permeability and myeloperoxidase (MPO) levels as well as the induction of the injurious pulmonary iNOS response. TRIF and Myd88 deficiency fully and partially attenuated T/HS lymph-induced increases in lung permeability respectively. Additional studies in TLR2 deficient mice showed that TLR2 activation was not involved in the pathology of T/HS lymph-induced lung injury. Lastly, the lymph samples were devoid of bacteria, endotoxin and bacterial DNA and passage of lymph through an endotoxin removal column did not abrogate the ability of T/HS lymph to cause lung injury in naïve mice. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that non-microbial factors in the intestinal mesenteric lymph after T/HS are capable of recreating T/HS-induced lung injury via TLR4 activation.

Anticoagulants influence the in vitro activity and composition of shock lymph but not its in vivo activity.

Many models of trauma-hemorrhagic shock (T/HS) involve the reinfusion of anticoagulated shed blood. Our recent observation that the anticoagulant heparin induces increased mesenteric lymph lipase activity and consequent in vitro endothelial cell cytotoxicity prompted us to investigate the effect of heparin-induced lipase activity on organ injury in vivo as well as the effects of other anticoagulants on mesenteric lymph bioactivity in vitro and in vivo. To investigate this issue, rats subjected to trauma-hemorrhage had their shed blood anticoagulated with heparin, the synthetic anticoagulant arixtra (fondaparinux sodium), or citrate. Arixtra, in contrast to heparin, did not increase lymph lipase activity or result in high levels of endothelial cytotoxicity. Yet, the arixtra-treated rats subjected to T/HS still manifested lung injury, neutrophil priming, and red blood cell dysfunction, which was totally abrogated by lymph duct ligation. Furthermore, the injection of T/HS mesenteric lymph, but not sham-shock lymph, collected from the arixtra rats into control mice recreated the pattern of lung injury, polymorphonucleocyte (PMN) priming, and red blood cell dysfunction observed after actual shock. Consistent with these observations, citrate-anticoagulated rats subjected to T/HS developed lung injury, and the injection of mesenteric lymph from the citrate-anticoagulated T/HS rats into control mice also resulted in lung injury. Based on these results, several conclusions can be drawn. First, heparin-induced increased mesenteric lymph lipase activity is not responsible for the in vivo effects of T/HS mesenteric lymph. Second, heparin should be avoided as an anticoagulant when studying the biology or composition of mesenteric lymph because of its ability to cause increases in lymph lipase activity that increase the in vitro cytotoxicity of these lymph samples.

Intravenous injection of mesenteric lymph produced during hemorrhagic shock decreases RBC deformability in the rat.

OBJECTIVE: To test the hypothesis that gut-derived factors carried in trauma-hemorrhagic shock (T/HS) lymph are sufficient to induce red blood cells (RBC) injury, to investigate their potential mechanisms of action, and to define the time post-T/HS that these factors appear in the lymph. METHODS: Mesenteric lymph collected from T/HS or trauma-sham shock (T/SS) rats over different time periods was injected intravenously into male rats at a rate of 1 mL/h for 3 hours. RBC deformability was measured using laser-assisted ektacytometer to calculate the elongation index. From the shear-stress elongation curve, the stress required for the erythrocytes to reach 50% of their maximal elongation was also determined. RBC deformability was measured before lymph infusion and at 1 hour and 3 hours after the initiation of lymph infusion. The effect of the lymph samples (5% v/v) was also determined in vitro by incubating naïve whole blood with the lymph samples. The potential role of T/HS lymph-induced RBC oxidant injury mediated by inducible nitric oxide synthase (iNOS)-generated oxidants and/or white blood cells (WBC) was investigated using iNOS inhibitors and WBC depletion, respectively. In all the in vivo studies, five to seven rats were studied per group. RESULTS: The intravenous injection of T/HS lymph but not T/SS lymph caused in vivo RBC injury. The biological activity of T/HS lymph varied over time with the RBC-injurious factors being produced only during the first 3 hours postshock. The in vivo inhibition of iNOS did not prevent lymph-induced RBC injury. T/HS lymph incubated in vitro with naïve whole blood resulted in RBC injury, but this injury was not observed in blood depleted of WBC. CONCLUSIONS: These results indicate that T/HS lymph produced during the initial 3-hour postshock period is sufficient to induce RBC injury in otherwise normal rats and that the lymph-induced RBC injury is not dependent on activation of the iNOS pathway but seems to require WBC.

The mucus layer is critical in protecting against ischemia-reperfusion-mediated gut injury and in the restitution of gut barrier function.

It is well documented that the gut injury plays a critical role in the development of systemic inflammation and distant organ injury in conditions associated with splanchnic ischemia. Consequently, understanding the mechanisms leading to gut injury is important. In this context, recent work suggests a protective role for the intestinal mucus layer and an injury-inducing role for luminal pancreatic proteases. Thus, we explored the role of the mucus layer in gut barrier function by observing how the removal of the mucus layer affects ischemia-reperfusion-mediated gut injury in rats as well as the potential role of luminal pancreatic proteases in the pathogenesis of gut injury. Ischemia was induced by the ligation of blood vessels to segments of the ileum for 45 min, followed by up to 3 h of reperfusion. The ileal segments were divided into five groups. These included a nonischemic control, ischemic segments exposed to saline, the mucolytic N-acetylcysteine (NAC), pancreatic proteases, or NAC + pancreatic proteases. Changes in gut barrier function were assessed by the permeation of fluorescein isothiocyanate dextran (molecular weight, 4,000 d) in ileal everted sacs. Gut injury was measured morphologically and by the luminal content of protein, DNA, and hemoglobin. The mucus layer was assessed functionally by measuring its hydrophobicity and morphologically. Gut barrier function was promptly and effectively reestablished during reperfusion, which was accompanied by the restoration of the mucus layer. In contrast, treatment of the gut with the mucolytic NAC for 10 min during ischemia resulted in a failure of mucus restitution and further increases in gut permeability and injury. The presence of digestive proteases by themselves did not exacerbate gut injury, but in combination with NAC, they caused an even greater increase in gut injury and permeability. These results suggest that the mucus layer not only serves as a barrier between the luminal contents and gut surface epithelia, but also plays a critical role in the maintenance and restitution of gut barrier function.

HIF-1 mediates pathogenic inflammatory responses to intestinal ischemia-reperfusion injury.

Acute lung injury (ALI) and the development of the multiple organ dysfunction syndrome (MODS) are major causes of death in trauma patients. Gut inflammation and loss of gut barrier function as a consequence of splanchnic ischemia-reperfusion (I/R) have been implicated as the initial triggering events that contribute to the development of the systemic inflammatory response, ALI, and MODS. Since hypoxia-inducible factor (HIF-1) is a key regulator of the physiological and pathophysiological response to hypoxia, we asked whether HIF-1 plays a proximal role in the induction of gut injury and subsequent lung injury. Utilizing partially HIF-1α-deficient mice in a global trauma hemorrhagic shock (T/HS) model, we found that HIF-1 activation was necessary for the development of gut injury and that the prevention of gut injury was associated with an abrogation of lung injury. Specifically, in vivo studies demonstrated that partial HIF-1α deficiency ameliorated T/HS-induced increases in intestinal permeability, bacterial translocation, and caspase-3 activation. Lastly, partial HIF-1α deficiency reduced TNF-α, IL-1ß, cyclooxygenase-2, and inducible nitric oxide synthase levels in the ileal mucosa after T/HS whereas IL-1ß mRNA levels were reduced in the lung after T/HS. This study indicates that prolonged intestinal HIF-1 activation is a proximal regulator of I/R-induced gut mucosal injury and gut-induced lung injury. Consequently, these results provide unique information on the initiating events in trauma-hemorrhagic shock-induced ALI and MODS as well as potential therapeutic insights.

Loss of the intestinal mucus layer in the normal rat causes gut injury but not toxic mesenteric lymph nor lung injury.

There is substantial evidence that gut barrier failure is associated with distant organ injury and systemic inflammation. After major trauma or stress, the factors and mechanisms involved in gut injury are unknown. Our primary hypothesis is that loss of the intestinal mucus layer will result in injury of the normal gut that is exacerbated by the presence of luminal pancreatic proteases. Our secondary hypothesis is that the injury produced in the gut will result in the production of biologically active mesenteric lymph and consequently distant organ (i.e., lung) injury. To test this hypothesis, five groups of rats were studied: 1) uninstrumented naive rats; 2) control rats in which a ligated segment of distal ileum was filled with saline; 3) rats with pancreatic proteases placed in their distal ileal segments; 4) rats with the mucolytic N-acetylcysteine (NAC) placed in their distal ileal segments; and 5) rats exposed to NAC and pancreatic proteases in their ileal segments. The potential systemic consequences of gut injury induced by NAC and proteases were assessed by measuring the biological activity of mesenteric lymph as well as gut-induced lung injury. Exposure of the normal intestine to NAC, but not saline or proteases, led to increased gut permeability, loss of mucus hydrophobicity, a decrease in the mucus layer, as well as morphological evidence of villous injury. Although proteases themselves did not cause gut injury, the combination of pancreatic proteases with NAC caused more severe injury than NAC alone, suggesting that once the mucus barrier is impaired, luminal proteases can injure the now vulnerable gut. Because comparable levels of gut injury caused by systemic insults are associated with gut-induced lung injury, which is mediated by biologically active factors in mesenteric lymph, we next tested whether this local model of gut injury would produce active mesenteric lymph or lead to lung injury. It did not, suggesting that gut injury by itself may not be sufficient to induce distant organ dysfunction. Therefore, loss of the intestinal mucus layer, especially in the presence of intraluminal pancreatic proteases, is sufficient to lead to injury and barrier dysfunction of the otherwise normal intestine but not to produce gut-induced distant organ dysfunction.