The systemic inflammatory response syndrome induces functional changes and relative hyporesponsiveness in neutrophils

Abstract

Purpose

To study the effects of systemic inflammatory response syndrome (SIRS) on polymorhonuclear neutrophil (PMN) function and phenotype by comparing neutrophils from critically ill patients with SIRS against those from healthy blood donors.

Material and Methods

Intensive care unit patients (n = 110) who met at least one SIRS criterion were recruited to the study. One hundred healthy blood donors were recruited as normal controls.

Results

Polymorphonuclear cells from critically ill patients with SIRS were more resistant to activation than PMNs from healthy donors, but when stimulated had an exaggerated microbicidal response. Buffer-treated PMNs from patients with SIRS had significantly higher CD43 surface expression that may inhibit heterotypic cellular contact or ligand stimulation of membrane receptors, had significantly lower expression of IgG receptor CD16, demonstrated resistance to shedding of L-selectin when primed by platelet-activating factor which could be pro-inflammatory, and had reduced respiratory burst when primed by platelet-activating factor than activated by formyl-Met-Leu-Phe.

Conclusion

The phenotypic and functional changes observed in neutrophils in the critically ill indicate that they require a higher level of stimulus to become activated. This may represent an auto-protective mechanism where the neutrophils in the already inflamed host may, by this mechanism, avoid excessive inflammation reducing the risk of further host cell injury and death.

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.