A Focus on SepsisThe systemic inflammatory response syndrome induces functional changes and relative hyporesponsiveness in neutrophils☆
Introduction
Sepsis remains one of the major health burdens in both the developed and developing world [1]. Sepsis may result in the initiation of the systemic inflammatory response syndrome (SIRS), and sepsis combined are responsible for more than 750 000 deaths per annum in the USA [2], with costs of treatment in excess of $15 billion annually. The immune response in sepsis involves both innate and adaptive immunity, and innate system dysfunction may facilitate invasion of the host by pathogenic microorganisms thereby diminishing the adaptive system's response.
Neutrophils (PMNs) have a pivotal microbicidal role in containing and destroying the causative foreign organisms after they have breached the host's anatomical barriers such as skin and mucosa [3]. In some situations, such as acute lung injury (ALI), this is a 2-step process where activation of the vascular endothelium results in pulmonary sequestration of PMNs [4]. These PMNs are then primed with an enhanced capacity to respond to injurious stimuli. Upon activation the sequestered PMNs release their microbicidal arsenal, resulting in cell injury and death. If this response is excessive or uncontrolled, it damages the host tissue causing capillary leak and ALI in the lungs [5]. PMN cell-mediated organ dysfunction is responsible for a significant component of the high morbidity and mortality seen in SIRS [6]. This early excess in inflammation is frequently followed by a relatively hypoinflammatory state labeled compensatory anti-inflammatory response syndrome, and the crossover period between the two as mixed anti-inflammatory response syndrome [7]. Inflammation is clearly an area of major cellular and humoral perturbations in the critically ill with significant cross talk between the innate and adaptive immune system. Currently, there are limited data of PMN functionality in these situations and no methods available to the clinician to assess PMN function in the critically ill. A clearer knowledge of the functionality of PMNs in migrating and killing organisms would be useful to the clinician in determining how the host is likely to respond (either excess or inadequate inflammation).
As the critically ill often experience PMN-mediated organ dysfunction, we hypothesized that PMNs of patients with SIRS would be hyperresponsive, such that agents which do not normally activate “quiescent PMNs” would cause activation. Moreover, PMNs isolated from patients with SIRS may exhibit augmented microbicidal responses particularly to activators of the NADPH oxidase [8], [9]. Thus, these PMNs would exhibit unique physiologic phenotypes, which would explain the altered immunity of patients with early SIRS. We therefore compared the expression of functional surface molecules (CD43, CD16, CD62L, CD11b, and CD18) of PMNs and the respiratory burst from 110 patients with SIRS against PMNs from 100 healthy blood donors.
Section snippets
Study Populations
Patients in the intensive care unit were included in the study if they demonstrated symptoms of the SIRS including (i) hypothermia (<36°C) or fever (>38°C), (ii) tachycardia (>90 beats per minute), (iii) hyperventilation (>20 breaths per minute or Paco2<32 mm Hg), and (iv) leucopenia (total leukocyte count <4000 mm3) or leucocytosis (total leukocyte count >12 000 mm3) [10]. Although the SIRS criteria have been criticized for being overly sensitive and nonspecific [11], in this study it provided
SIRS patients' PMNs have increased CD43 expression
Patient PMNs (n = 66) had significantly higher (median ± SEM) CD43 expression (3.37 × 105 ± 0.95 CD43 ABC/PMN) than the controls (2.44 × 105 ± 1.14 CD43 ABC/PMN) (n = 80) (Fig. 1). To assess the relationship between CD43 expression and inflammation, results were stratified according to SIRS criteria. CD43 expression was significantly increased in all patients who met at least one SIRS criterion; however, no significant difference was detected between the various SIRS groups (data not shown).
Discussion
The data demonstrated that circulating PMNs from patients with SIRS manifest a relative state of hyporesponsiveness compared to PMNs from healthy donors. Importantly, these PMNs were neither effete nor functionally hyperreactive. SIRS evoked an atypical PMN phenotype as evidenced by the altered expression of key surface molecules essential for the physiologic response of PMNs to infection, including significantly higher expression of CD43, a naturally anti-adhesive molecule; reduced expression
Conclusion
By comparing PMN phenotype and function in a large cohort of patients with SIRS against a large cohort of healthy blood donors, we observed both pro- and anti-activation phenotypic changes and speculate that an auto-protective mechanism is at work in SIRS. Most of the PMN functions appear intact but require an augmented stimulus for activation and release of the microbicidal arsenal. In addition, the role of CD43 surface expression warrants further study as a PMN response marker which may
Acknowledgment
We would like to thank Genghis Lopez for performing the soluble CD62L assays and the nursing staff of the John B McCarthy Intensive Care Unit, The Prince Charles Hospital.
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Financial support: This work was supported by an Australian RedCross Blood Service, Internal Research Grant.