Inflammation
Early systemic inflammation is the hallmark of sepsis. Sepsis begins with two simultaneous factors:

• Identification of infection byproducts released from the invading microbes
• Recognition of warning signals by cell surface receptors on specific populations of immune, epithelial and endothelial cells

These byproducts and warning signals are known as pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). PAMPs and DAMPs bind to receptors on a subpopulation of immune, epithelial and endothelial cells. These receptors include:

• Toll-like receptors
• nucleotide-binding oligomerization domain (NOD)-like receptors
• Retinoic acid-inducible gene (RIG)-like receptors
• mannose-binding lectin and scavenger receptors

Binding of these receptors ignites signaling pathways involved in inflammatory and immune responses. Specific fragments of invading organisms (bacteria, fungi, etc) and injured tissue recruit pro-inflammatory intermediates to the infected region. These intermediates then activate a variety of proteins, such as mitogen-activated protein kinases (MAPKs), Janus kinases (JAKs) or signal transducers and activators of transcription (STATs) and nuclear translocation of nuclear factor-κΒ (NF-κΒ), that activate expression of early activation genes.  

The pro-inflammatory intermediate NF-κΒ activates several early activation genes of inflammatory cytokines including:

• Tumor necrosis factor (TNF)
• IL-1
• IL-12
• IL-18
• type I interferons (IFNs)

These cytokines then activate the second group of inflammatory cytokines and chemokines such as:

• IL-6
• IL-8
• IFNγ
• CC-chemokine ligand 2 (CCL2)
• CCL3
• CXC-chemokine ligand 10 (CXCL10)

Activation of these cytokines alters expression of pro- and anticoagulant proteins such as:

• thrombomodulin
• tissue factor
• von Willebrand factor
• plasminogen activator inhibitor 1 (PAI-1)
• activated protein C

The result is endothelial cells taking on a procoagulant state which promotes sepsis.

The C5a–C5a receptor axis
PAMPs and DAMPs also promote complement activation, resulting in the generation of complement peptides C3a and C5a. C5a is the most active inflammatory peptide during sepsis. It has been linked to several contributors of sepsis including:

• neutrophil dysfunction
• lymphoid cell apoptosis
• enhanced systemic inflammation
• cardiomyopathy
• disseminated intravascular coagulation (DIC) (a condition that causes small blood clots)
• complications due to multiple organ failures

C5a attracts neutrophils, monocytes, and macrophages to the infected region. Once it reaches the infected site, C5a induces neutrophil oxidative burst causing the release of reactive oxygen species. C5a also causes granular enzymes to be released, which contribute to inflammatory tissue injury. C5a promotes the synthesis and release of proinflammatory cytokines, as well.  Several animal studies have found that C5a contributes to organ damage related to inflammation and blocking the activity of C5a with antibodies can reduce the severity of sepsis, suggesting it may be a potential target for sepsis therapies.

Immune Suppression
Immunosuppression occurs during both the early and late stages of sepsis and may even occur during inflammation. Chronic immunosuppression and inflammation are called persistent inflammation/immunosuppression and catabolism syndrome or PICS. PICS is defined by increased expression of a C-reactive protein, neutrophilia, and release of underdeveloped myeloid cells. Persistent inflammation is different from the immediate inflammation associated with sepsis. The cause of persistent inflammation is not well-understood. Some hypotheses include that it is ignited by DAMPs or alarmins produced from fragments of damaged tissue (i.e. mitochondrial DNA, histones, ATP, etc). Persistent inflammation may also take advantage of changes in the microbiota of the host or other reactions to the infection. A driver of immunosuppression is apoptosis. A large portion of T cells, B cells, and dendritic cells undergo apoptosis in patients with sepsis. The level of lymphocyte apoptosis is directly correlated with the severity of sepsis. Lymphocyte apoptosis also indirectly contributes to sepsis because the phagocytes released to remove the apoptotic cells lead to the release of anti-inflammatory cytokines and reduces expression of genes encoding pro-inflammatory cytokines. In patients with sepsis, there is also an increase in the number of immature neutrophils and myeloid-derived suppressor cells or MDSCs. Immature neutrophils and MDSCs release several anti-inflammatory cytokines. Antigen-presenting cells (APCs) also lose expression of the major histocompatibility complex (MHC) in certain cells which reduces their responsiveness.

Endothelial barrier dysfunction, Coagulation and Clot Formation
The endothelial barrier lines blood vessels to separate fluid blood from the tissue lining. It allows the exchange of gases, nutrients and other components between the blood and tissue. In the early stages of sepsis and septic shock, the barrier begins to dysfunction. The barrier is supported by several molecules and proteins including adhesion molecules and the cell cytoskeleton. However, during sepsis, the inflammatory mediators and toxins that are released, along with an increase in expression of integrins and selectins and the binding of leukocytes to endothelial cells and platelets disrupt these structures. The barrier becomes more permeable as the layer of glycoprotein that supports the anticoagulant nature of the barrier breaks down in sepsis. This layer is particularly common in organ tissue, which could account for the multiple organ failures seen in this condition. As mentioned previously, sepsis promotes coagulation in multiple ways including a breakdown of the endothelial barrier. Anticoagulants in the host are downregulated. Surprisingly, this can lead to uncontrolled bleeding. Clot formation is a natural response to injury. Following injury, endothelial cells express adhesion molecules that bind to leukocytes and platelets, causing coagulation. Cytokines in early inflammation induce expression of receptors that bind to these endothelial molecules in lymphocytes, platelets, and myeloid cells.