Pathogenesis of infection in surgical patients

Abstract

Purpose of review: Despite the application of prophylactic antimicrobial therapy and advanced technologies, infection remains one of the most common causes of morbidity and mortality in surgical patients. Understanding the pathogenesis of surgical infection would offer new insights into the development of biomarkers to predict and stratify infection in patients, and to explore specific strategies to minimize this serious postoperative complication.

Recent findings: The acute nonspecific inflammatory response triggered by endogenous danger signals evoked by surgical insult is beneficial, while paradoxically associated with reduced resistance to infection. There is growing evidence indicating that primed inflammation by surgical insult exaggerates the dysregulation of the immune-inflammatory response to the invasion of pathogens postoperatively. Innate immune receptors, such as Toll-like receptors (TLRs), contribute to detecting both pathogen-associated molecular patterns and endogenous damage-associated molecular patterns, and to further amplifying inflammatory responses to infection. Current evidence shows the fascinating role of non-TLRs in the process of infection. Non-TLRs, such as membrane-associated triggering receptor expressed on myeloid cells family, cytosolic nucleotide-binding oligomerization domain-like receptors and nuclear receptor nuclear family 4 subgroup A receptors, are also crucial in triggering the immune responses and mounting an effective defense against surgical insults and the second hit of infection.

Summary: Understanding the pivotal role of non-TLRs in sensing exogenous and endogenous molecules, and the influence of primed systemic inflammation and depressed immune status on the defense against pathogen after surgical insult, would be helpful to fully explore the relevant sophisticated phenomena of surgical infection, and to elucidate the occurrence of heterogeneous constellations of clinical signs and symptoms among this special population.

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FIGURE 1

Immune-inflammatory response model in patients with surgical infection, medical infection and surgical insult. The Y axis represents the level of immune-inflammatory response. The ebb represents a dynamic change of the immune-inflammatory status. Tissue damage, as well as a stress humoral and neural response, evoked by operative insult can mobilize danger-associated molecular patterns (DAMPs) and alarmins which subsequently spillover into the circulation, activate immune cells and then lead to overwhelming inflammatory processes [–22]. Accompany with the increased nonspecific inflammatory response, the surgical patients’ ability to mount an effective defense against invading pathogens is suppressed which increases the susceptibility to infection [11,12]. In surgical patients, DAMPs and alarmins can act synergistically with pathogen-associated molecular patterns (PAMPs) to further stimulate immune cells, and further lead to deteriorative proinflammatory response and immunosuppression with an increased risk of multiorgan dysfunction and death [,,,–26].

FIGURE 2

Both Toll-like receptors (TLRs) and non-TLRs can sense PAMPs from invading pathogens and/or DAMPs released from stressed or damaged cells, trigger various intracellular signaling pathways to upregulate/downregulate the transcription of specific genes, and further modulate immune-inflammatory response. DAMPs, danger-associated molecular patterns; PAMPs, pathogen-associated molecular patterns.

FIGURE 3

The TREMs signaling pathway during the course of immune-inflammatory response. TREMs associated with the DNAX activation protein-12 (DAP-12) chain subunit can activate phosphatidylinositol 3-kinase (PI3K), the phosphorylation of phospholipase (PL) Cγ and extracellular signal-related kinase (ERK)1/2 [–49]. TREM-1 can act as an amplifier of the systemic inflammatory response syndrome associated with infection [–54]. TREM-2 can act as a negative regulator inhibiting TLR-mediated inflammatory response, and enhance the host's ability to eradicate damaged cells and invading pathogens [–61]. TREMs, triggering receptor expressed on myeloid cells.