Acute Inflammation

Acute inflammation is the body's immediate and complex defense mechanism against injury or infection, involving a rapid deployment of immune cells and signaling molecules. This process is a critical function of the immune system, designed to prevent further harm and initiate healing. The four cardinal signs of acute inflammation are heat, redness, pain, and swelling, which are traditionally referred to as calor, rubor, dolor, and oedema in Latin.

 

What Triggers Acute Inflammation?

The inflammatory process kicks off when tissue damage occurs, whether from physical injury, bacterial or viral infection, or harmful chemical exposure. Damaged cells release a series of alarm signals, particularly signaling proteins known as cytokines, along with other antimicrobial substances. These signals alert the immune system, calling immune cells like phagocytes to the site of injury or infection. Phagocytes are a type of white blood cell that can engulf and destroy harmful pathogens, playing a pivotal role in the initial defense.

 

 The Body's Response to Injury

Once the immune system is activated, a chain reaction occurs, involving several chemicals released by immune cells. These substances include leukotrienes, prostaglandins, histamine, kinins, and anaphylotoxins, which all contribute to the characteristic features of inflammation:

• Vasodilation: The affected area’s blood vessels widen, or dilate, increasing blood flow. This vasodilation leads to the visible redness and heat.
• Increased Vascular Permeability: Blood vessel walls become more permeable, allowing immune cells and vital proteins to exit the bloodstream and move into the damaged tissue. This process results in the accumulation of fluid, causing the swelling (edema) that accompanies inflammation.
• Pain: Swelling and the release of certain chemicals irritate nerve endings, resulting in pain. Prostaglandins are among the substances responsible for amplifying this pain sensation.

 

Systemic Effects of Inflammation

While acute inflammation usually remains localized, it can also have widespread effects on the body. Key inflammatory mediators like interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) are involved in these systemic effects. When these cytokines reach the brain, they act on the hypothalamus, causing a rise in body temperature (fever). Fever, in turn, helps to enhance immune cell efficiency and hinder the growth of certain pathogens.

These cytokines also prompt the liver to produce acute phase proteins. These proteins play crucial roles in the body’s defense mechanisms and help to regulate the inflammatory response.

 

Acute Phase Proteins

Acute phase proteins are produced by the liver in response to inflammation and serve several vital functions in managing the body’s defense and healing processes. Their levels can increase rapidly in the bloodstream during an acute inflammatory reaction.

Key Acute Phase Proteins and Their Functions

1. C-reactive Protein (CRP) and Serum Amyloid A: These proteins can increase significantly during acute inflammation. CRP, in particular, binds to microbes, marking them for destruction by immune cells, and also aids in tissue repair.
2. Fibrinogen: This protein is involved in blood clotting and helps form a clot at the site of injury, effectively sealing wounds and preventing blood loss. It also plays a role in the structural support of new tissue.
3. α1-Antitrypsin and α1-Antichymotrypsin: These proteins regulate the activity of enzymes released by immune cells, preventing excessive tissue damage during inflammation.

 

Antioxidant and Iron-Scavenging Proteins

Inflammation produces reactive molecules called oxygen free radicals, which can damage cells. Antioxidant proteins like haptoglobin and manganese superoxide dismutase neutralize these harmful radicals. Additionally, iron-binding proteins, such as transferrin, ferritin, and lactoferrin, limit the availability of iron to bacteria, which need iron to grow. By sequestering iron, these proteins slow down bacterial proliferation.

 

Role of Immunoglobulins

Although immunoglobulins, or antibodies, are not acute phase proteins, they contribute to inflammation, particularly in chronic cases. They help neutralize pathogens and facilitate their removal from the body, bolstering the immune system's response.

 

Resolution of Inflammation

The resolution of inflammation is as critical as the initial response. It ensures that the body does not suffer excessive tissue damage or develop chronic inflammation, which can have long-term health consequences. The resolution phase is an active and regulated process that helps return tissues to their normal state.

How Inflammation Resolves

The process begins with stopping the production of pro-inflammatory signals. This shutdown is necessary to prevent the immune system from attacking healthy tissue. Neutrophils, the first immune cells to arrive at the site of inflammation, are programmed to die through a process called apoptosis once their task is complete. Macrophages, another type of immune cell, then arrive to clear the debris. These cells engulf and digest dead neutrophils, pathogens, and damaged tissue.

 

Cleaning Up and Repairing Damage

Macrophages play a dual role. Besides clearing out dead cells and debris, they release enzymes like collagenase and elastase that break down damaged connective tissue. This creates room for new, healthy tissue to form. Macrophages also release cytokines that drive the healing process. Key cytokines involved in tissue repair include:

• Transforming Growth Factor-beta (TGF-β): This molecule helps attract fibroblasts, which are cells responsible for producing collagen, a structural protein essential for wound healing.
• Platelet-Derived Growth Factor (PDGF): This factor promotes tissue growth and repair.
• Angiogenic Factors: These substances stimulate the growth of new blood vessels, ensuring an adequate supply of oxygen and nutrients to the healing tissue.
• The coordinated activity of immune cells and signaling molecules ensures that inflammation resolves properly and that tissue repair occurs efficiently, restoring the normal function of the affected area.

 

Complications: Sepsis and Septic Shock

When the inflammatory response becomes unregulated or overly aggressive, it can lead to severe complications like sepsis and septic shock. These are life-threatening conditions characterized by a widespread inflammatory response that damages organs and tissues.

 

Understanding Sepsis and Septic Shock

In sepsis, the immune system's response to an infection spirals out of control, causing inflammation throughout the body. Septic shock is a more severe stage, in which inflammation leads to dangerously low blood pressure and impaired organ function. During septic shock, macrophages release a large amount of pro-inflammatory cytokines, overwhelming the body's regulatory mechanisms.

 

Mechanism of Septic Shock

Blood Vessel Damage and Fluid Loss: Hyperactivated neutrophils release enzymes and oxygen free radicals into the bloodstream. These substances damage the lining of blood vessels, making them more permeable. As a result, fluid leaks from the blood vessels, causing swelling and further reducing blood volume and blood pressure.

2. Organ Damage and Failure: The widespread inflammation activates the body's clotting system, leading to the formation of clots in small blood vessels. This impairs blood flow, causing tissue damage and increasing the risk of organ failure. Clots can block the supply of oxygen and nutrients to vital organs, contributing to multi-organ failure.

 

Common Outcomes and Risks

• Cardiovascular Collapse: The heart struggles to maintain adequate blood flow, leading to circulatory failure.
• Acute Respiratory Distress Syndrome (ARDS): Fluid accumulation in the lungs decreases oxygen exchange, making breathing difficult.
• Disseminated Intravascular Coagulation (DIC): This condition involves widespread clotting followed by excessive bleeding due to the depletion of clotting factors.
• Multi-Organ Failure: When critical organs like the kidneys, liver, or lungs fail, the risk of death increases significantly.

 

Causes and Triggers

Sepsis is often caused by infections with Gram-negative bacteria, which have components like lipopolysaccharides (LPS) in their cell walls that trigger an intense immune response. However, other bacterial, viral, or fungal infections can also result in sepsis and septic shock.

 

Conclusion

Acute inflammation is a crucial part of the body's defense and healing processes. It effectively contains threats and initiates repair, but it must be carefully regulated to prevent harm to healthy tissues. The body’s ability to resolve inflammation and heal efficiently is vital for maintaining overall health. However, when inflammation becomes dysregulated, as seen in sepsis and septic shock, the consequences can be dire, underscoring the importance of timely medical intervention.