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(Chest. 1999;116:1709-1715.)
© 1999 American College of Chest Physicians

Pulmonary Neutrophil Accumulation Following Human Endotoxemia*

Manabu Kinoshita, MD; Hidetaka Mochizuki, MD and Satoshi Ono, MD

* From the Department of Surgery I, National Defense Medical College, 3-2, Namiki, Tokorozawa, Saitama, 359, Japan.

Correspondence to: Manabu Kinoshita, MD. Department of Surgery, Gifu Military Hospital, Gifu Air Base, Naka, Kakamihara, Gifu, 504-8701, Japan; e-mail: ishi2{at}ylw.mmt.or.jp


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Objective: To elucidate the role of pulmonary neutrophil accumulation in the pathogenesis of human acute lung injury (ALI) following endotoxemia.

Design: Retrospective study.

Setting: Surgical unit in a tertiary-care university hospital.

Patients: Thirty-three patients who died of intra-abdominal sepsis and received an autopsy.

Measurements: Just before each patient’s death, (1) plasma endotoxin was determined by the limulus gelation test, and (2) the severity of ALI was estimated by the Murray lung injury score. (3) Neutrophil accumulation in the pulmonary microcirculation was evaluated in the autopsy specimens using a computerized picture analysis method.

Results: (1) Endotoxin-positive patients were more likely to fall into the severe lung injury group (endotoxin-positive patients, 38% vs endotoxin-negative patients, 0%; p < 0.01). (2) The endotoxin-positive patients exhibited significantly higher neutrophil accumulation in the pulmonary microcirculation than endotoxin-negative patients (8,349 ± 984/mm2 vs 4,047 ± 447/mm2, respectively; p < 0.01). (3) Severe lung injury patients with endotoxemia had almost the same degree of neutrophil accumulation in the pulmonary microcirculation as mild-to-moderate lung injury patients with endotoxemia (8,338 ± 1,622/mm2 vs 8,359 ± 1,290/mm2, respectively), showing a significant higher neutrophil accumulation compared to no lung injury patients without endotoxemia (5,102 ± 410/mm2; p < 0.01).

Conclusion: Endotoxemia might cause ALI and pulmonary neutrophil accumulation. Pulmonary neutrophil accumulation might not be enough to cause severe lung injury (ARDS), although it is necessary to cause ALI, because the degree of pulmonary neutrophil accumulation did not correlate with the severity of ALI.

Key Words: acute lung injury • ARDS • autopsy study • endotoxemia • neutrophil accumulation


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Gram -negative sepsis is frequently complicated by acute lung injury (ALI), and it remains a major cause of mortality in such septic patients.1 Suffredini et al2 have reported that injections of endotoxin, a component of Gram-negative bacterial walls, provoked dysfunction of gas exchange and increased lung permeability in human volunteers. These findings suggest that endotoxin might participate in the pathogenesis of ALI. Many investigators have reported that IV injection of endotoxin to animals induces not only acute noncardiogenic edema, but also neutrophil accumulation in the lung.3 4 5 6 These studies suggest that neutrophils play an important role in ALI induced by endotoxin.

Several reports have revealed a predominant increase of neutrophils in BAL fluid (BALF) obtained from patients with the most severe form of ALI, ARDS.7 8 Several pathologic studies also have demonstrated prominent neutrophil sequestration and migration into interstitial and alveolar spaces of the lung at autopsy in patients with ARDS.9 10 11 Results of these human studies do not conflict with those of experimental studies using animal models. Nevertheless, there are few precise quantitative studies that especially focus on pulmonary neutrophil accumulation in patients with endotoxemia. In this clinical study, we investigated quantitatively neutrophil accumulation in the pulmonary microcirculation in patients with ALI following endotoxemia, to elucidate the role of neutrophils in the pathogenesis of ALI following endotoxemia.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patients
Thirty-three patients who received an autopsy were included in this investigation. The 27 men and 6 women ranged in age from 30 to 84 years. They had been admitted to the Department of Surgery I at the National Defense Medical College Hospital for various gastroenterologic diseases and died of intra-abdominal sepsis between September 1983 and December 1994 (Table 1 ). All registered patients underwent a determination of plasma endotoxin and peripheral neutrophil count, and evaluation of ALI just before death. The culture examinations were also performed in all patients at the same time as the determination of plasma endotoxin. No Gram-positive infection was found in any culture examinations.


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  		Table 1.. Data on Patients With Intra-abdominal Sepsis

 
This investigation was performed in accordance with the ethical standards of the Committee on Human Experimentation of the National Defense Medical College and the Helsinki Declaration of 1975.

Methods
Endotoxin Determination: Plasma endotoxin was determined in all registered patients by the limulus lysate gelation method.12 In 31 patients, blood samples for endotoxin determination were obtained during the agonal period at the same time as both the determination of the peripheral neutrophil count and the evaluation of ALI. The agonal period meant a time within a few hours before death. In the other two patients, whose infectious conditions had been quite stable until their deaths, the determination of endotoxin was performed using samples obtained 4 or 5 days before death. Samples were collected in sterile, pyrogen-free glass tubes containing 3.8% sodium citrate (1.3 x 105 mol/L blood). They were then centrifuged at 1,000g for 40 s to obtain platelet-rich plasma and stored at - 80°C until assayed.

Proteins were first removed from stored specimens by adding one-fourth volume chloroform and vigorously mixed for 1 h at room temperature (25°C). Emulsions of chloroform and plasma were separated into three layers by centrifugation at 500g for 10 min. The middle cloudy layer was then extracted for endotoxin determination.

Endotoxin was detected by mixing 0.1 mL of limulus amebocyte lysate (Pregel-S; Seikagaku Kogyo; Tokyo, Japan) and 0.1 mL of the deproteinized material and incubating for 4 h at 37°C. Development of a marked increase in gelation at shaking of a sample was interpreted as evidence for the presence of endotoxin. Mixtures with unchanged gelation following incubation were interpreted as negative. False-positive reactions were eliminated by excluding patients with chronic hepatitis, cirrhosis, or fungal infection.

Evaluation of ALI: The severity of ALI was objectively evaluated during the agonal period at the same time as the determination of peripheral neutrophil count, using the Murray lung injury score.13 This score was obtained by grading the following clinical parameters on a scale of 0 to 4: the extent of chest infiltration on radiographs, the ratio of arterial oxygen tension to inspired oxygen concentration, the positive end-expiratory pressure, and pulmonary compliance. The overall lung injury score was derived by dividing the total score by the number of criteria evaluated. "No lung injury" was defined as a score 0, "mild-to-moderate lung injury" as 0.1 to 2.5, and "severe lung injury" as > 2.5.

The patients were classified into the following three groups according to the severity of lung injury during the agonal period: "no," "mild-to-moderate," and "severe." Patients with underlying pulmonary disease and with any signs of upper respiratory infections on physical examination, chest radiograph, or bacteriologic examination of sputum were excluded from this study. Patients with lung injury of > 1-week duration were also excluded because we focused only on ALI in this study.

Evaluation of Neutrophil Accumulation in the Pulmonary Microcirculation: At autopsy, lung specimens were fixed by injecting 10% formalin into the primary bronchi at a pressure of 100 cm and then immersing in 10% formalin for about 5 days. Microscopic slides were prepared from formalin-fixed, paraffin-embedded sections of the pulmonary tissue and stained with hematoxylin and eosin.

Ten sections of the left upper pulmonary lobe of each patient showing the most typical histopathologic changes were photographed using 35-mm film (X100). Each picture was scanned by the Nikon Coolscan Control 1.2-J scanner (Nikon; Tokyo, Japan) and obtained as a file in Adobe Photoshop 3.0-J software (Adobe Systems; Mountain View, CA). Then, each file was transferred to Aldus Persuasion 3.0-J software (Adobe Systems) to estimate pulmonary neutrophil accumulation precisely. Neutrophils in the capillary and postcapillary vessels, defined as the pulmonary microcirculation, were counted on each image of the pulmonary tissue (Fig 1 , top). The area of the pulmonary microcirculation was estimated as follows: all vessel lumens of the image on Aldus Persuasion 3.0-J were traced, and the total cross-sectional traced areas were then calculated using the TOSPIX picture analysis package (Toshiba; Tokyo, Japan; Fig 1 , bottom). Neutrophil accumulation in the pulmonary microcirculation was quantified in each image by dividing the neutrophil count by the vascular area, and the average value of 10 fields was calculated for each patient.



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  		Figure 1.. The images of the pulmonary tissue. Top: Neutrophils in the pulmonary capillary and postcapillary vessels were counted on this image (hematoxylin-eosin x 100). Bottom: The areas of the pulmonary capillary and postcapillary vessels were traced on the same image (shown as black areas). Neutrophil accumulation in the pulmonary microcirculation was quantified by dividing the neutrophil count by the traced areas in the same image.

 
Evaluation of Circulating Neutrophils: Blood samples were taken from veins of the upper extremities during the agonal period at the same time as the evaluation of ALI, and neutrophil counts were obtained by routine laboratory tests.

Statistics: Data are expressed as mean ± SEM. One-way analysis of variance was used to evaluate group differences in neutrophil counts. The {chi}2 test was used to demonstrate a relationship between endotoxemia and the severity of ALI. The correlation between neutrophil count in the pulmonary microcirculation and circulating neutrophil count was evaluated by Pearson’s coefficient. For all statistical tests, a p value < 0.05 was considered significant.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Both of the patients who underwent a determination of plasma endotoxin using blood samples obtained 4 or 5 days before death were endotoxin negative. Their infectious conditions had been quite stable and not been changed until their deaths. Therefore, their conditions could be considered as endotoxin negative when they underwent the determination of circulating neutrophil count and the evaluation of ALI at the agonal period. Both of them exhibited no lung injury, and their circulating neutrophil counts were within the normal range at the agonal period.

Relationship Between Endotoxemia and Severity of ALI
Eight of the 21 patients in the endotoxin-positive group exhibited severe lung injury, 13 exhibited mild-to-moderate lung injury, and none exhibited no lung injury. None of the 12 patients in the endotoxin-negative group had severe lung injury, 7 had mild-to moderate lung injury, and 5 had no lung injury. The endotoxin-positive group was significantly more likely to have severe lung injury than the endotoxin-negative group (p < 0.01; Table 2 ).


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  		Table 2.. Relationship Between Endotoxemia and Severity of ALI*

 
Relationship Between Endotoxemia and Neutrophil Accumulation in the Pulmonary Microcirculation or Circulating Neutrophil Count
In the endotoxin-positive group, neutrophil accumulation in the pulmonary microcirculation was significantly higher than that of the endotoxin-negative group (8,349 ± 984/mm2 vs 4,047 ± 447/mm2; p < 0.01; Fig 2 , left, a). The circulating neutrophil count, however, showed no significant difference between the endotoxin-positive and endotoxin-negative groups (12,629 ± 1,633/µL vs 11,193 ± 1,708/µL; not significant; Fig 2 , right, b).



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  		Figure 2.. Neutrophil counts in the endotoxin-positive and endotoxin-negative groups. Left, a: Neutrophil counts in the pulmonary microcirculation. The neutrophil count in the pulmonary microcirculation was significantly higher in the endotoxin-positive group than that in the endotoxin-negative group. Right, b: Circulating neutrophil counts. There was no significant difference between the endotoxin-positive and endotoxin-negative groups. Bars indicate SEMs; ns = not significant.

 
Relationship Between Severity of ALI and Neutrophil Accumulation in the Pulmonary Microcirculation in the Endotoxin-Positive or Endotoxin-Negative Groups
The severe lung injury with endotoxin-positive group showed the almost same neutrophil accumulation in the pulmonary microcirculation as the mild-to-moderate lung injury with endotoxin-positive group: severe lung injury with endotoxemia, 8,338 ± 1,622/mm2 vs mild-to-moderate lung injury with endotoxemia, 8,359 ± 1290/mm2. These two endotoxin-positive groups showed significantly higher neutrophil accumulations in the pulmonary microcirculation than the no lung injury with endotoxin-negative group (no lung injury, 2,781 ± 763/mm2; p < 0.01, respectively), and exhibited a high tendency of neutrophil accumulation in the pulmonary microcirculation compared to the mild-to-moderate lung injury with endotoxin-negative group, which was 5,102 ± 410/mm2 (Fig 3 , left, a).



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  		Figure 3.. Neutrophil counts by the severity of the ALI. Left, a: Neutrophil count in the pulmonary microcirculation. The neutrophil counts in the pulmonary microcirculation of the two endotoxin-positive lung injury groups were significantly higher than that of the no lung injury with endotoxin-negative group. Right, b: Circulating neutrophil counts. There was no significant differences among four groups. Bars indicate SEMs.

 
Relationship Between Severity of ALI and Circulating Neutrophil Count in the Endotoxin-Positive or Endotoxin-Negative Groups
There were no differences in circulating neutrophil count among the following four groups: severe lung injury patients with endotoxemia, 12,661 ± 3,089/µL; mild-to-moderate lung injury patients with endotoxemia, 13,235 ± 1,609/µL; mild-to-moderate lung injury patients without endotoxemia, 12,447 ± 2,235/µL; and no lung injury patients without endotoxemia, 10,824 ± 1,694/µL (Fig 3 , right, b).

Correlation Between Neutrophil Count in the Pulmonary Microcirculation and Circulating Neutrophil Count
The neutrophil count in the pulmonary microcirculation did not correlate with the circulating neutrophil count (Fig 4 ).



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  		Figure 4.. Correlation between neutrophil counts in the pulmonary microcirculation and the systemic circulation. There was no correlation between these values.

 
Pulmonary Histopathologic Findings in Endotoxemia
In all endotoxin-positive patients, remarkable sequestration of neutrophils in the pulmonary capillaries and postcapillaries, as well as interstitial edema, were observed (Fig 5 ). Alveolar edema was observed in 90% of the endotoxin-positive patients. Congestion of the pulmonary capillaries was also observed in 86%. Hyaline membranes were seen in 29%. A dramatic increase in intra-alveolar macrophages was seen in 52%. These pathologic changes were more severe in the severe lung injury patients than the mild-to-moderate lung injury patients with endotoxemia. Neither interstitial fibrosis nor severe leukocyte infiltration in the alveolar space could be found in all patients with endotoxemia.



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  		Figure 5.. Histopathologic findings in a patient with endotoxemia and severe lung injury. Neutrophils were found in the pulmonary capillaries and postcapillaries. Severe alveolar edema and capillary congestion were also observed (hematoxylin-eosin x 400).

 

   Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Gram-negative septicemia has stubbornly eluded vigorous therapy and still has high mortality. This is because we cannot thoroughly control endotoxin-related complications of septicemia like ARDS. It is important to reveal the mechanism of ARDS following endotoxemia for improving the poor prognosis of Gram-negative septicemia.

It is well known that there is a broad range of sensitivity to endotoxin among mammals and organs. For example, endotoxin can cause circulatory shock in anesthetized dogs at a dose that does not produce severe lung injury.14 In unanesthetized sheep, a similar dose of endotoxin that is too small to cause shock produces severe lung injury.15 The systemic response of humans to endotoxin appears to be much more sensitive than these animals. Endotoxin usually has been given to human volunteers at a dose of 2 to 4 ng/kg or 20 U/kg as an IV bolus injection. These doses of endotoxin usually provoke mild but variable responses characteristic of Gram-negative sepsis in human.2 16 17 18 In animal studies, endotoxin is usually given in quantities at least 100 times those given to human volunteers.14 15 Therefore, the findings derived from experimental models of endotoxemia in animals should be cautiously applied to human endotoxemia. Ideally, studies to elucidate the role of neutrophils in ALI following endotoxemia should be performed in human subjects.

Powe et al19 has reported the pulmonary accumulation of neutrophils in four ARDS patients by using a radionuclide scanning technique. This study clarified neutrophil accumulation clinically but did not show any relation to endotoxemia. Our study provided direct evidence of neutrophil pulmonary accumulation in endotoxemia. Since the patients in our study had no underlying pulmonary disease, ALI was considered to be derived from abdominal sepsis. So these patients were suitable for studying the influences of endotoxin on the lung. It is impossible to perform open lung biopsy for such patients, so we evaluated pulmonary specimens obtained at autopsy.

Once endotoxin enters the body, it activates neutrophils, macrophages, endothelia, and complements.20 21 22 Martich et al16 and Kuhns et al17 have reported that injections of endotoxin to volunteers could provoke increases of interleukin 8 (IL-8) and other cytokines, such as tumor necrosis factor-{alpha} and interleukin-1ß. Donnelly et al23 have reported high IL-8 concentrations in the BALF of ARDS patients, as well as IL-8 expression by alveolar macrophages using immunohistochemistry. It also has been reported that human endothelia release IL-8 in vitro.24 25 Pulmonary tissue contains tremendous numbers of alveolar macrophages and capillary vessels that can produce IL-8. So in human endotoxemia, the lung may be exposed to high concentrations of IL-8 released from those cells, causing abundant neutrophil migration to the lung. Endotoxin and evoked cytokines also could induce adhesion molecules including endothelial leukocyte adhesion molecule-1, intercellular adhesion molecule-1 on the surface of endothelia, and macrophage-1 and lymphocyte function-associated antigen-1 on neutrophils.26 27 28 29 Schleimer et al30 and Read et al31 have reported that endotoxin and cytokines promote neutrophil adherence on endothelium in vitro. In human endotoxemia, neutrophils migrating to the lung may adhere to pulmonary capillary vessels under these adhesion molecules rich condition.

In the present study, neutrophil accumulation in the pulmonary microcirculation was significantly higher in the patients with endotoxemia, whereas the circulating neutrophil count did not significantly increase. Moreover, there was no correlation between these two. In some of the registered patients, we determined neutrophil elastase, which was a complex with {alpha}-1 protease inhibitor, or superoxide anion derived from circulating neutrophil. Those factors did not correlate with the circulating neutrophil count but tended to correlate with the degree of neutrophil accumulation in the lung (data were not shown). We think that the most important factor for neutrophil accumulation in the lung is not the number of circulating neutrophil but their activated potential. Some patients complicated bone marrow suppression due to severe sepsis. It might be also one of the reasons for the no correlation between the circulating neutrophil count and the degree of neutrophil accumulation in the lung.

Suffredini et al2 have pointed out that alveolar neutrophils obtained from BALF of volunteers injected with endotoxin did not increase in spite of the emergence of mild pulmonary dysfunction. In the present study, we also found few neutrophils in the alveolar spaces in severe lung injury, even though many neutrophils accumulated in the pulmonary microcirculation. These findings suggest that most of the neutrophils migrating to the lung remain in the pulmonary microcirculation and do not enter the alveolar spaces. The increase of neutrophils in the pulmonary microcirculation appears to be much more important in the pathophysiology of ALI than those in the alveolar spaces.

Although we found significant neutrophil accumulation in the pulmonary microcirculation of the patients with endotoxemia, there was no difference in its degree between the severe and the mild-to-moderate lung injury patients with endotoxemia. The severity of the lung injury did not seem to be related only to the degree of neutrophil accumulation in the pulmonary microcirculation. Not only the accumulation of neutrophils but also neutrophil-derived bioactive substances such as elastase and superoxide anion might be related to deteriorate the lung injury to a more severe condition like ARDS.

Endotoxin can activate complements that are thought to cause ARDS.22 32 33 Several investigators have suggested that complements activated by endotoxin cause the aggregation of neutrophils and leukoemboli in the lung, resulting in ARDS.34 35 However, we found few leukoemboli but many sequestrated neutrophils in the pulmonary microcirculation in patients with ALI. On the other hand, Moore et al18 have reported that neutrophils may be activated by administrating endotoxin to volunteers without concurrent complement activation. Therefore, a neutrophil chemotactic factor IL-8 or neutrophil-endothelium adhesion molecules (endothelial leukocyte adhesion molecule-1, intercellular adhesion molecule-1, macrophage-1, lymphocyte function-associated antigen-1, etc.), rather than leukoemboli, may be primarily responsible for neutrophil pulmonary accumulation seen in ALI following endotoxemia.

In conclusion, significant neutrophil accumulation in the pulmonary microcirculation was found in the patients with endotoxemia, who all were complicated by ALI. Whereas the degree of pulmonary neutrophil accumulation was not related to the circulating neutrophil count nor the severity of ALI, endotoxemia might cause pulmonary neutrophil accumulation in human. Although this accumulation might be necessary to cause ALI, it does not seem to be enough to deteriorate the lung injury to severe lung injury (ARDS).


   Footnotes
 
Abbreviations: ALI = acute lung injury; BALF = BAL fluid; IL-8 = interleukin 8

Received for publication December 15, 1998. Accepted for publication August 10, 1999.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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