Sepsis

What is sepsis?

Sepsis is a severe and potentially life-threatening condition that occurs when the body’s response to an infection triggers a widespread inflammatory reaction throughout the body. It can lead to organ dysfunction, shock, and death if not promptly treated. Sepsis can affect people of all ages, but it is most common and dangerous in older adults, infants, and individuals with weakened immune systems.

 

The process of sepsis typically begins with an infection caused by bacteria, viruses, fungi, or parasites. Common sources of infection include pneumonia, urinary tract infections, abdominal infections (such as appendicitis or diverticulitis), skin infections, and bloodstream infections (bacteremia). When the immune system detects the presence of pathogens, it mounts a response to fight the infection. However, in some cases, the immune response becomes dysregulated, leading to systemic inflammation and tissue damage.

 

Sepsis can progress to severe sepsis or septic shock if left untreated. Severe sepsis occurs when there is evidence of organ dysfunction or tissue hypoperfusion, while septic shock is characterized by profound hypotension despite adequate fluid resuscitation. Both conditions are medical emergencies and require immediate intervention.

 

What is the relationship between sepsis and oxidative stress?

The relationship between sepsis and oxidative stress is significant and plays a crucial role in the pathophysiology of sepsis-induced organ dysfunction and tissue injury. Oxidative stress refers to an imbalance between the production of reactive oxygen species (ROS) and the body’s antioxidant defense mechanisms, leading to cellular damage and dysfunction. Several mechanisms contribute to oxidative stress during sepsis:

 

• Immune Response: Sepsis triggers a systemic inflammatory response as the body attempts to combat the infection. Inflammatory cells, such as neutrophils and macrophages, produce ROS as part of the immune defense mechanism to destroy invading pathogens. However, excessive ROS production can overwhelm antioxidant defenses and lead to oxidative damage to surrounding tissues.

 

• Mitochondrial Dysfunction: Sepsis disrupts mitochondrial function, leading to impaired cellular respiration and ATP production. Dysfunction of the electron transport chain within mitochondria results in the leakage of electrons, leading to the generation of ROS. Additionally, mitochondrial DNA damage and release of mitochondrial components into the cytoplasm contribute to ROS production and exacerbate oxidative stress.

 

• Endothelial Dysfunction: Sepsis-induced endothelial dysfunction contributes to microvascular dysfunction, increased vascular permeability, and tissue hypoperfusion. ROS-mediated injury to endothelial cells disrupts nitric oxide (NO) signaling, leading to vasoconstriction, platelet aggregation, and leukocyte adhesion. These processes further impair tissue perfusion and exacerbate organ dysfunction.

 

• Antioxidant Depletion: Sepsis leads to the depletion of endogenous antioxidants, such as glutathione, superoxide dismutase, and catalase, due to increased ROS production and decreased antioxidant enzyme activity. This imbalance between ROS generation and antioxidant defense mechanisms results in oxidative stress and cellular damage.

 

• Activation of Inflammatory Pathways: Inflammatory mediators released during sepsis, such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), and interleukin-6 (IL-6), can activate intracellular signaling pathways that promote ROS production and oxidative stress. Activation of nuclear factor-kappa B (NF-kB) and mitogen-activated protein kinase (MAPK) pathways leads to the upregulation of ROS-generating enzymes and downregulation of antioxidant genes, further exacerbating oxidative stress.

 

• Tissue Injury and Organ Dysfunction: Oxidative stress-induced damage to cellular components, including lipids, proteins, and DNA, contributes to tissue injury and organ dysfunction in sepsis. ROS-mediated lipid peroxidation, protein oxidation, and DNA damage disrupt cellular function and integrity, leading to cell death, organ dysfunction, and multi-organ failure.

 

Overall, oxidative stress plays a central role in the pathophysiology of sepsis and contributes to the development of sepsis-induced organ dysfunction and tissue injury.