Reactive oxygen species (ROS) and iron play important roles in the innate immune response. ROS are released by immune cells and are highly reactive and indiscriminately destructive in response to pathogens. In addition, ROS act as signaling molecules and play a role in apoptosis, therefore excessive ROS production can damage host molecules, leading to more harm than benefit for the host. Iron acts as a catalyst for the formation of ROS, therefore, manipulation of iron levels is a way in controlling ROS production. Iron metabolism and ROS production may affect many disease processes and must be tightly regulated for the host to generate an appropriate response. Current researches examine the roles of iron and ROS in various conditions, including neurodegeneration, inflammation, infection and cancer. Therapies directed at regulating ROS production through regulating iron levels are a major focus in these fields today.

The urinary system, primarily responsible for the filtration of blood and waste, is affected by several infectious and inflammatory conditions. Focusing on the lower tract, this review outlines the physiological and immune landscape of the urethra and bladder, addressing key immunological and microbiological aspects of important infectious/inflammatory conditions. The conditions addressed include urethritis, interstitial cystitis/bladder pain syndrome, urinary tract infections, and urosepsis. Key aspects of each condition are addressed, including epidemiology, pathophysiology, and clinical considerations. Finally, therapeutic options are outlined, highlighting gaps in the knowledge and novel therapeutic approaches.

Iron is an essential element in multiple biochemical pathways in humans and pathogens. As part of the innate immune response in local infection, iron availability is restricted locally in order to reduce overproduction of reactive oxygen species by the host and to attenuate bacterial growth. This physiological regulation represents the rationale for the therapeutic use of iron chelators to support induced iron deprivation and to treat infections. In this review paper we discuss the importance of iron regulation through examples of local infection and the potential of iron chelation in treating infection.

Beta-caryophyllene has demonstrated anti-inflammatory effects in a variety of conditions, including interstitial cystitis. These effects are mediated primarily via the activation of the cannabinoid type 2 receptor. Additional antibacterial properties have recently been suggested, leading to our investigation of the effects of beta-caryophyllene in a murine model of urinary tract infection (UTI). Female BALB/c mice were intravesically inoculated with uropathogenic Escherichia coli CFT073. The mice received either beta-caryophyllene, antibiotic treatment using fosfomycin, or combination therapy. After 6, 24, or 72 h, the mice were evaluated for bacterial burden in the bladder and changes in pain and behavioral responses using von Frey esthesiometry. In the 24 h model, the anti-inflammatory effects of beta-caryophyllene were also assessed using intravital microscopy. The mice established a robust UTI by 24 h. Altered behavioral responses persisted 72 h post infection. Treatment with beta-caryophyllene resulted in a significant reduction in the bacterial burden in urine and bladder tissues 24 h post UTI induction and significant improvements in behavioral responses and intravital microscopy parameters, representing reduced inflammation in the bladder. This study demonstrates the utility of beta-caryophyllene as a new adjunct therapy for the management of UTI.

Iron is an essential element for various physiological processes, but its levels must remain tightly regulated to avoid cellular damage. Similarly, iron plays a dual role in systemic inflammation, such as with sepsis. Leukocytes utilize iron to produce reactive oxygen species (ROS) to kill bacteria, but pathologically increased iron-catalyzed ROS production in sepsis can lead to damage of host cells, multi-organ failure and death. Temporary reduction in bioavailable iron represents a potential therapeutic target in sepsis. This study investigates the effect of the novel iron chelator, DIBI, in murine models of systemic (hyper-)inflammation: C57BL/6 mice were challenged with toxins from Gram-positive (Staphylococcus aureus: lipoteichoic acid, peptidoglycan) and Gram-negative bacteria (Escherichia coli and Klebsiella pneumoniae: lipopolysaccharide). Intravital microscopy (IVM) was performed to assess immune cell activation and its impact on microvascular blood flow in vivo in the microcirculation of the gut. Plasma inflammatory mediators were measured via multiplex assay, and morphologic change in intestinal tissue was evaluated. DIBI treatment decreased leukocyte (hyper-)activation induced by Gram-positive and Gram-negative toxins. In some cases, it preserved capillary perfusion, reduced plasma inflammatory markers and attenuated tissue damage. These findings support the utility of DIBI as a novel treatment for systemic inflammation, e.g., sepsis.

Because of its unique microvascular anatomy, the intestine is particularly vulnerable to microcirculatory disturbances. During inflammation, pathological changes in blood flow, vessel integrity and capillary density result in impaired tissue oxygenation. In severe cases, these changes can progress to multiorgan failure and possibly death. Microcirculation may be evaluated in superficial tissues in patients using video microscopy devices, but these techniques do not allow the assessment of intestinal microcirculation. The gold standard for the experimental evaluation of intestinal microcirculation is intravital microscopy, a technique that allows for the in vivo examination of many pathophysiological processes including leukocyte-endothelial interactions and capillary blood flow. This review provides an overview of changes in the intestinal microcirculation in various acute and chronic inflammatory conditions. Acute conditions discussed include local infections, severe acute pancreatitis, necrotizing enterocolitis and sepsis. Inflammatory bowel disease and irritable bowel syndrome are included as examples of chronic conditions of the intestine.