Reactive oxygen species (ROS) are key signaling molecules that play an important role in the progression of inflammatory disorders. An enhanced ROS generation by polymorphonuclear neutrophils (PMNs) at the site of inflammation causes endothelial dysfunction and tissue injury. The vascular endothelium plays an important role in passage of macromolecules and inflammatory cells from the blood to tissue. Under the inflammatory conditions, oxidative stress produced by PMNs leads to the opening of inter-endothelial junctions and promotes the migration of inflammatory cells across the endothelial barrier. The migrated inflammatory cells not only help in the clearance of pathogens and foreign particles but also lead to tissue injury. The current review compiles the past and current research in the area of inflammation with particular emphasis on oxidative stress-mediated signaling mechanisms that are involved in inflammation and tissue injury.

Reactive Oxygen Species in Inflammation and Tissue Injury

It has been known for many years that neutrophils and platelets participate in the pathogenesis of severe sepsis, but the inter-relationship between these players is completely unknown We report several cellular events that led to enhanced trapping of bacteria in blood vessels: platelet TLR4 detected TLR4 ligands in blood and induced platelet binding to adherent neutrophils This led to robust neutrophil activation and formation of neutrophil extracellular traps (NETs) Plasma from severely septic humans also induced TLR4-dependent platelet-neutrophil interactions, leading to the production of NETs The NETs retained their integrity under flow conditions and ensnared bacteria within the vasculature The entire event occurred primarily in the liver sinusoids and pulmonary capillaries, where NETs have the greatest capacity for bacterial trapping We propose that platelet TLR4 is a threshold switch for this new bacterial trapping mechanism in severe sepsis

Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood

The inflammatory bowel diseases (IBDs), Crohn's disease and ulcerative colitis, are chronic inflammatory disorders of the gastrointestinal tract. Enormous progress has been made recently in understanding the pathogenesis of these diseases. Through the study of patients and mouse models, it has emerged that Crohn's disease is driven by the production of interleukin-12 (IL-12) and interferon-gamma (IFN-gamma), whereas ulcerative colitis is probably driven by the production of IL-13. A second area of progress is in the identification of specific genetic abnormalities that are responsible for disease. The most important finding is the identification of mutations in the gene that encodes NOD2 (nucleotide-binding oligomerization domain 2) protein in a subgroup of patients with Crohn's disease. Here, we discuss these recent findings and the implications for therapy.

The immunological and genetic basis of inflammatory bowel disease.

Microbial Influences in Inflammatory Bowel Diseases

The microvascular endothelial cell monolayer localized at the critical interface between the blood and vessel wall has the vital functions of regulating tissue fluid balance and supplying the essential nutrients needed for the survival of the organism. The endothelial cell is an exquisite "sensor" that responds to diverse signals generated in the blood, subendothelium, and interacting cells. The endothelial cell is able to dynamically regulate its paracellular and transcellular pathways for transport of plasma proteins, solutes, and liquid. The semipermeable characteristic of the endothelium (which distinguishes it from the epithelium) is crucial for establishing the transendothelial protein gradient (the colloid osmotic gradient) required for tissue fluid homeostasis. Interendothelial junctions comprise a complex array of proteins in series with the extracellular matrix constituents and serve to limit the transport of albumin and other plasma proteins by the paracellular pathway. This pathway is highly regulated by the activation of specific extrinsic and intrinsic signaling pathways. Recent evidence has also highlighted the importance of the heretofore enigmatic transcellular pathway in mediating albumin transport via transcytosis. Caveolae, the vesicular carriers filled with receptor-bound and unbound free solutes, have been shown to shuttle between the vascular and extravascular spaces depositing their contents outside the cell. This review summarizes and analyzes the recent data from genetic, physiological, cellular, and morphological studies that have addressed the signaling mechanisms involved in the regulation of both the paracellular and transcellular transport pathways.

https://www.physiology.org/doi/pdf/10.1152/physrev.00012.2005

Signaling Mechanisms Regulating Endothelial Permeability

Goblet cells reside throughout the length of the small and large intestine and are responsible for the production and maintenance of the protective mucus blanket by synthesizing and secreting high-molecular-weight glycoproteins known as mucins. To elucidate the role of goblet cells in the biology of the intestinal tract, an overview of the physiological implications of the mucus gel is presented, including a concise review of the products secreted by the cell. Because of the unique nature of this highly polarized exocrine cell, the maturational reorganization of the cytoarchitecture and the cellular mechanisms by which goblet cells secrete their products are discussed. This includes elucidation of the baseline secretory pathway, which is dependent on the cytoskeleton for granule movement, and the accelerated secretory pathway, which is independent of the cytoskeleton but requires an extracellular signal to occur. Finally, the involvement of goblet cell mucins in the pathophysiology of intestinal neoplasia and ulcerative colitis are presented.

Functional biology of intestinal goblet cells

• Experiments were performed in mice to determine whether endotoxin could cause bacteria normally colonizing the gut to spread systemically, a process termedbacterial translocation. Endotoxin given intraperitoneally promoted bacterial translocation in a dose-dependent fashion from the gut to the mesenteric lymph node (MLN). The incidence of bacterial translocation to the MLN was similar whether the endotoxin was administered intramuscularly or intraperitoneally, although the number of bacteria colonizing the MLN was greater with intraperitoneal endotoxin. The incidence and magnitude of endotoxin-induced bacterial translocation were similar between CD-1 and C3H/HeJ (endotoxin-resistant) mice, indicating that bacterial translocation is not prevented by genetic resistance to endotoxin. Thus, it appears that the gut may serve as a reservoir for bacteria causing systemic infections during endotoxemia. (Arch Surg1987;122:185-190)

https://jamanetwork.com/journals/surg/articlepdf/592285/archsurg_122_2_008.pdf

Endotoxin promotes the translocation of bacteria from the gut.

Sepsis and multiple organ failure are common after hemorrhagic shock. The goal of the current experiments was to determine whether hemorrhagic shock would promote the translocation of bacteria from the gut to visceral organs. Twenty-four hours after being subjected to sham shock, or 30, 60, or 90 minutes of shock (30 mm Hg), rats were sacrificed and their organs quantitatively cultured for translocating bacteria. There was a direct relationship between the duration of hemorrhagic shock and the 24-hour mortality rate (p = 0.02). Bacteria did not translocate from the gut in the sham-shock rats, but did translocate to the mesenteric lymph nodes, livers, and spleens of the rats subjected to hemorrhagic shock (p less than 0.01). Rats subjected to 90 minutes of shock shock exhibited a greater degree of bacterial translocation than rats receiving 30 or 60 minutes of shock (p less than 0.05). The most common translocating bacteria were Escherichia coli and Enterococcus. Hemorrhagic shock injured the gut mucosa and caused subepithelial edema and focal areas of necrosis. Thus hemorrhagic shock followed by reinfusion of shed blood disrupts the gut barrier and allows indigenous bacteria normally contained within the gut to cause systemic infections.

Hemorrhagic shock induces bacterial translocation from the gut.

The objective of this study was to characterize the mechanisms of acute and chronic intestinal mucosal injury and inflammation induced by subcutaneously injected indomethacin (Indo). One injection of Indo (7.5 mg/kg) produced acute injury and inflammation in the distal jejunum and proximal ileum that were maximal at three days and completely resolved within one week. Two daily subcutaneous injections of Indo produced a more extensive and chronic inflammation that lasted in an active form in more than 75% of the rats for at least two weeks. Epithelial injury, as measured by enhanced mucosal permeability, was significantly elevated only at one day in the acute model (one injection) but was persistently elevated in the chronic model (two injections). Bile duct ligation completely attenuated increased mucosal permeability in the acute model, however, depletion of circulating neutrophils had no effect. Neither Indo (0-0.1 mg/ml) nor normal bile was cytotoxic to cultured rat intestinal epithelial cells; however, they synergistically promoted significant cytotoxicity. Bile collected from rats treated with Indo was cytotoxic towards the epithelial cells in a dose-dependent manner. Sulfasalazine and metronidazole (100 mg/kg/day, both) attenuated enhanced mucosal permeability in the chronic model. Massive bacterial translocation into the mesenteric lymph nodes, liver, and spleen following two injections of Indo was significantly attenuated by metronidazole. We conclude that: (1) a single injection of Indo produces acute intestinal mucosal injury and inflammation that resolve completely within three to seven days, whereas two daily injections of Indo produce both acute and chronic injury and inflammation, (2) enterohepatic circulation of Indo is important in promoting the acute phases of injury and inflammation, (3) circulating neutrophils do not play a role in the pathogenesis of this model, and (4) endogenous bacteria play an important role in exacerbating and/or perpetuating the chronic phases of injury and inflammation.

Mechanisms of acute and chronic intestinal inflammation induced by indomethacin

Experiments were performed to determine if obstructive jaundice promotes the translocation of bacteria from the gastrointestinal tract to visceral organs. Three groups of mice were studied: control (n=20), sham ligated (n=28), and bile duct ligated (n=33). The sham-ligated group underwent laparotomy and manipulation of the portal region, whereas the ligated group had their common bile ducts ligated. Seven days later, the mice were killed, their organs cultured, and the gastrointestinal tract examined histologically. The bilirubin levels of the ligated group (18.7 mg/dL) were elevated compared with the other groups (0.5 mg/dL) (p

Robert D. Specian

Papers

Functional biology of intestinal goblet cells

Endotoxin promotes the translocation of bacteria from the gut.

Hemorrhagic shock induces bacterial translocation from the gut.

Mechanisms of acute and chronic intestinal inflammation induced by indomethacin

Obstructive jaundice promotes bacterial translocation from the gut