Original article
Neutrophil elastase and systemic inflammatory response syndrome in the initiation and development of acute lung injury among critically ill patients

https://doi.org/10.1016/j.biopha.2007.07.003Get rights and content

Abstract

Critically ill patients are commonly associated with systemic inflammatory response syndrome (SIRS) and are at a greater risk of developing acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Under these conditions, large amounts of various cytokines are produced, which either directly or indirectly induce tissue injury and finally organ dysfunctions, through the activation of neutrophils and as a result of release of cytotoxic molecules, especially neutrophil elastase (NE). In the present study, we determined plasma neutrophil elastase–alpha-1 antitrypsin complex (NE–AT) and elastase digests of cross-linked fibrin (e-XDP) in critically ill patients to elucidate the significance of NE in the initiation and progression of ALI and ARDS in the presence or absence of SIRS. We found significantly increased levels of plasma NE–AT in the patients with ARDS, especially when the definition of SIRS was met. Among ALI/ARDS groups, plasma NE–AT, but not e-XDP, correlated significantly with the decrease in PaO2/FIO2 ratio and the duration of ALI/ARDS. Furthermore, NE–AT, but not e-XDP, significantly increased in subgroups whose PaO2/FIO2 ratio decreased by more than 20%. Such correlations and differences between the subgroups were not observed in the non-ALI patients. From these results, we speculate that NE–AT, but not e-XDP, may be predictive of progressive lung injury in the early stage of ALI and ARDS.

Introduction

Patients in a critical condition, especially those suffering from severe sepsis, are commonly associated with systemic inflammatory response syndrome (SIRS) [1]. These patients are at greater risk of developing multiple organ dysfunction syndrome (MODS), including acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), which is currently the major determinant of their prognosis [2]. However, there is only a small fraction of the available evidence for the treatments [3], such as early fluid resuscitation [4], tight glucose control [5], activated protein C [6] for severe sepsis and low tidal volume ventilation for ALI/ARDS [7]. There is therefore a clear need to accumulate further clinical evidence for sepsis and septic ALI/ARDS is being awaited.

In SIRS and sepsis, various proinflammatory and anti-inflammatory cytokines are produced in large quantities, and this either directly or indirectly induces tissue injury and finally organ dysfunction [8]. Neutrophils are intensely activated by multiple stimuli, such as bacterial toxins and endogenous proinflammatory mediators, and play key roles in inducing tissue injury and the resulting organ dysfunctions through the release of various cytotoxic molecules, including reactive oxygen intermediates and granular enzymes. Among these, neutrophil elastase (NE), a serine proteinase, is thought to be one of the major cytotoxic molecules because of its abundance and powerful degrading activity against a wide variety of substrates [9]. In addition, NE has recently become known for its proinflammatory functions [10]. Since NE is harmful even to the host, there exist multiple defensive mechanisms to neutralize free NE. In blood, alpha-1 antitrypsin (AT) and alpha-2 macroglobulin are abundant, and intravascularly released NE is immediately neutralized. In contrast, although there exist NE inhibitors in the extravascular space, such as AT, secretory leukocyte protease inhibitor (SLPI) and elafin, the concentrations of these endogenous protease inhibitors of high molecular weight may be insufficient to adequately neutralize extravascularly released NE, especially when a large amount of NE is released in patients with SIRS and sepsis [11].

Neutrophils exist mostly within the circulation and either float in or are loosely attached to the peripheral vasculature under physiological conditions, but they easily migrate out of capillaries in response to various stimuli. NE can be released either intravascularly or extravascularly, but the place where NE is released is critical in the induction of tissue injury and organ dysfunction. However, thus far, there has been no method or marker to indicate where NE is released, and a plasma marker for extravascularly released NE is eagerly awaited as it would enable prediction of the degree of NE-induced tissue injury, especially in patients with SIRS. We hypothesized that plasma levels of elastase digests of cross-linked fibrin (e-XDP) correlate with the amount of extravascularly released NE, especially in the lungs, and thus may be useful in predicting the degree of lung injury. In the present study, we determined plasma levels of NE–AT complex and e-XDP in critically ill patients, and examined their significance in ALI and ARDS.

Section snippets

Study population

We conducted a single-center retrospective observational study at the university hospital of the School of Medicine, Keio University. The study population included 136 patients, who were admitted to our intensive care unit, followed up for more than 7 days, and whose blood was drawn on the day of admission. The study has been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki. There were 94 men and 42 women (mean ± SEM age, 60.9 ± 1.4 years). Sixty-four

Patient characteristics

Of the 136 patients, 112 were placed in the non-ALI category, 16 in the ALI category, and eight in the ARDS category. Ninety-seven patients (71.3%) fulfilled the criteria of SIRS and 80 patients (58.8%) fulfilled the criteria of sepsis on the day of inclusion in the study. On the day of inclusion, the mean APACHE II score of the patients was 9.6 ± 0.5 (range 0–31), the mean SOFA score was 5.1 ± 0.3 (range 0–16), and the mean MODS score was 3.0 ± 0.3 (range 0–14). Mortality at discharge was 8.1%.

Plasma levels of NE–AT and e-XDP in non-ALI, mild ALI, and ARDS

Fig. 1

Discussion

In the present study, we examined plasma NE–AT and e-XDP levels in critically ill patients to elucidate the significance of NE in the initiation and progression of ALI and ARDS in the presence or absence of SIRS. We found significantly increased levels of plasma NE–AT in the patients with ARDS, especially when the definition of SIRS was met. Among the ALI/ARDS groups, the plasma NE–AT levels, but not the e-XDP levels, correlated significantly with the decrease between the initial and lowest P/F

Acknowledgements

We thank Ms. Satoko Mino and Ms. Mieko Hayakawa for collecting clinical data. This study was supported in part by Grants-in-Aid from the Japanese Ministry of Education, Culture, Sports, Science and Technology, Keio Gijuku Fukuzawa Memorial Fund for the Advancement of Education and Research, and a research grant from Ono Pharmaceuticals.

References (19)

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1

Present address: Division of Emergency Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan

2

Present address: International University of Health and Welfare, Department of Preventive Health Examination Center in Sanno Hospital, Tokyo, Japan

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