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J Appl Physiol 83: 1090-1095, 1997;
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Journal of Applied Physiology
Vol. 83, No. 4, pp. 1090-1095, October 1997
CELLULAR ASPECTS OF LUNG FUNCTION

Experimental murine acid aspiration injury is mediated by neutrophils and the alternative complement pathway

Martin R. Weiser1, Taine T. V. Pechet1, Julian P. Williams1, Minghe Ma2, Paul S. Frenette3, Francis D. Moore1, Lester Kobzik2, Richard O. Hines4, Denisa D. Wagner3, Michael C. Carroll2, and Herbert B. Hechtman1

Departments of 1 Surgery and 2 Pathology, Brigham and Women's Hospital, and 3 The Center for Blood Research, The Harvard Medical School, Boston 02115-0001; and 4 The Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139

ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
ACKNOWLEDGEMENTS
FOOTNOTES
REFERENCES

ABSTRACT

Weiser, Martin R., Taine T. V. Pechet, Julian P. Williams, Minghe Ma, Paul S. Frenette, Francis D. Moore, Lester Kobzik, Richard O. Hines, Denisa D. Wagner, Michael C. Carroll, and Herbert B. Hechtman. Experimental murine acid aspiration injury is mediated by neutrophils and the alternative complement pathway. J. Appl. Physiol. 83(4): 1090-1095, 1997.---Acid aspiration may result in the development of the acute respiratory distress syndrome, an event associated with significant morbidity and mortality. Although once attributed to direct distal airway injury, the pulmonary failure after acid aspiration is more complex and involves an inflammatory injury mediated by complement (C) and polymorphonuclear leukocytes. This study examines the injurious inflammatory cascades that are activated after acid aspiration. The role of neutrophils was defined by immunodepletion before aspiration, which reduced injury by 59%. The injury was not modified in either P- or E-selectin-knockout mice, indicating that these adhesion molecules were not operative. C activation after aspiration was documented with immunochemistry by C3 deposition on injured alveolar pneumocytes. Animals in which C activation was inhibited with soluble C receptor type 1 (sCR1) had a 54% reduction in injury, similar to the level of protection seen in C3-knockout mice (58%). However C4-knockout mice were not protected from injury, indicating that C activation is mediated by the alternative pathway. Finally, an additive effect of neutrophils and C was demonstrated whereby neutropenic animals that were treated with sCR1 showed an 85% reduction in injury. Thus acid aspiration injury is mediated by neutrophils and the alternative C pathway.

complement activation; transgenic mice; inflammation; pneumonia; selectins

INTRODUCTION

ASPIRATION OF ACIDIC gastric contents into distal airways and alveoli occurs in patients with altered mental status, abnormal swallowing mechanisms, or abnormal bowel motility, settings that accompany stroke, induction of anesthesia, and drug intoxication. After an aspiration event, patients develop dyspnea, hypoxemia, and diffuse pulmonary infiltrates in the setting of low pulmonary capillary wedge pressures. These are the hallmarks of the acute respiratory distress syndrome. Mortality after major aspiration is significant, ranging between 30 and 94% in published reports (1, 7, 17).

Early studies describing the pathophysiology of acid aspiration involved instillation of 1-4 ml/kg of 0.1 N HCl into the canine trachea, producing transient apnea and copious, protein-rich bronchial secretions. The instilled acid was neutralized within 10 min. The subsequent response of hypoxia, increased microvascular permeability, and intravascular volume depletion led to hemoconcentration, hypotension, and uniform mortality by 5 h (1). The authors ascribed the injury to direct distal airway and alveolar damage by the instilled acid.

Later studies have described a biphasic response, composed of an early direct pulmonary injury due to acid, followed by a delayed inflammatory injury mediated by polymorphonuclear leukocytes (PMNs). The second component was shown in experiments of PMN depletion before aspiration, which reduced lung injury by 66% (14). Injury-derived, locally produced chemoactivators such as eicosanoids (9-11) and interleukins (5) were thought to recruit and activate the PMNs, leading to their transmigration to alveolar spaces and bronchial walls (4). Experimental inhibition of the above-mentioned agents reduced leukosequestration and injury. The mechanism by which PMNs caused injury beyond that, because of the direct effects of acid, was thought to be release of peroxides and proteases (14) that damaged pneumocytes, endothelium, and basement membranes, accounting for the capillary leak syndrome after aspiration.

Complement (C) is also suspected to play a role in amplifying lung injury after acid aspiration because inhibition of C activation with soluble C receptor type 1 (sCR1) reduced pulmonary injury (18) in a rat model of aspiration. sCR1 is the genetically engineered molecule composed of the extracellular portion of CR1, which promotes the dissociation of the C3 and C5 convertases (25), as well as the binding and degradation of C4b and C3b, thereby inhibiting both the alternative and classic C pathways. The mechanism by which C is activated after aspiration has not been defined, nor is the way in which C activation aggravates the injury. In general, C promotes inflammation via soluble and cell-bound activation fragments. The soluble fragments (C3a and C5a) act as anaphylotoxins, causing PMN recruitment, adhesion, and activation. Cell-bound fragments such as the membrane attack complex (C5b-9) cause cell injury or osmotic lysis or may act as adhesion molecule counterreceptors, as in the case iC3b.

This study examines the self-destructive actions of inflammatory mediators in acid aspiration lungs, specifically the relative roles of PMNs and C in mediating the injury. We show that PMN depletion reduces the injury by 59%. On the other hand, animals deficient in either P- or E-selectin were not protected. Animals in which C activation was prevented with sCR1 had a 54% reduction in injury indexes, similar to the level of protection achieved in animals genetically deficient in C3 (58%). Animals genetically deficient in C4, a classic pathway complement protein component, were not protected. Finally, animals that were neutrophil depleted and treated with sCR1 showed an additive, 85% reduction in injury indexes.

METHODS

Mice. Male C57BL/6 mice were used for PMN-depletion and C-inhibition experiments. C3-, C4- (27), P-selectin- (15), and E-selectin-deficient mice (8) were generated by gene targeting via homologous recombination in embryonic stem cells. All knockout strains were shown not to express any detectable level of the proteins encoded by the respective targeted genes. Animals used in this study were maintained in accord with the guidelines of the Committee on Animals of the Harvard Medical School and those prepared by the Committee on the Care and Use of Laboratory Animals of the Institute of Laboratory Animal Resources, National Research Council [DHHS publication no. (NIH) 85-23, Revised 1985].

Aspiration protocol. Mice weighing 20-25 g were anesthetized with intraperitoneal pentobarbital sodium (60 mg/kg), weighed, and their necks were washed with ethanol swabs. Through a midline neck incision, a 16-gauge tracheostomy tube (Angiocath, Becton-Dickinson, Sandy, UT) was placed and secured with 4-0 silk sutures. The tracheostomy was cannulated with a 22-gauge angiocath and 2 ml/kg of 0.1 N HCl (Sigma Chemical, St. Louis, MO), or 0.9% saline (sham) was instilled into the trachea by using a 1-ml syringe. Preliminary studies showed the injury to plateau when 2 ml/kg were instilled. At this dose, the least variability was noted (Fig. 1). Five minutes before aspiration, 1 µCi 125I-albumin (ICN, Irving, CA) in 0.1 ml of 0.9% saline was infused intravenously via a tail vein. Mice were maintained in a supine position and were kept anesthetized by intermittent intraperitoneal pentobarbital sodium injection. They were covered throughout the experiment to maintain body temperature.
Fig. 1. Acid aspiration-induced lung injury is related to volume of 0.1 N HCl instilled into trachea. n = 5 Animals/group. An injury plateau was reached with minimal variability at 2 ml/kg. Bars, SD.
[View Larger Version of this Image (8K GIF file)]

Four hours after aspiration, the animals were euthanized by an intraperitoneal pentobarbital sodium overdose (90 mg/kg). Through a midline sternotomy, blood was aspirated from the right ventricle, the lungs were removed. Each lung was weighed, and radioactivity was measured. The lungs were then dried in a 90°C convection oven for 72 h, and their dry weight was measured. Lung permeability index (PI) is reported as the ratio of radioactivity per gram dry lung to radioactivity per gram blood. An identical preparation, excluding the administration of 125I-albumin, was used for immunohistochemical analysis of C deposition. In this group of animals, the trachea and lungs were inflated with optimal cutting-temperature compound (Miles) and immediately frozen.

PMN depletion. Mice were rendered PMN depleted by an intraperitoneal injection of rabbit anti-mouse PMN antibody (40 mg/kg; Accurate, Westbury, NY) 16 h before acid aspiration. Venous blood samples were taken just before and 4 h after acid aspiration, before euthanasia. The blood was used for leukocyte counting and blood smears. To ensure that the immunodepletion of PMNs did not simultaneously activate and consume C components, a group of mice was treated with the anti-PMN antibody, and serum C3 levels were measured.

C inhibition with sCR1. Both classic and alternative pathway C activation were inhibited by an intravenous bolus of sCR1 (T-Cell Sciences, Needham, MA) administered 5 min before acid aspiration. Each animal received 20 mg/kg of sCR1, a dose previously determined to effectively inhibit C activation.

C inhibition in neutrophil-depleted mice. Animals were rendered PMN-depleted with an intraperitoneal injection of anti-PMN antibody (40 mg/kg) 16 h before acid aspiration. C activation was inhibited by the intravenous administration of sCR1 (20 mg/kg) 5 min before aspiration. Blood samples for total leukocyte counts and differentials were taken when animals were euthanized.

C3 immunostaining. Immunoperoxidase labeling of C3 was performed on paraformaldehyde-fixed, cryostat sections of lung by using goat anti-mouse C3 (5 mg/ml; Organon Teknia, Durham, NC) and a standard avidin-biotin protocol (24). Controls included use of irrelevant goat immunoglobulin (Ig) G (5 mg/ml) and immunostaining of lung samples from sham mice.

Statistical analysis. Results are presented as means ± SE in the text, Figs. 1-3, and Table 1. Groups were compared by using a Student's t-test. For multiple comparisons, data were subjected to analysis of variance and the Student-Newman-Keuls test. Percent reduction in PI was calculated after subtraction of the background value determined in sham animals that were instilled with saline.
Fig. 2. Acid aspiration-induced lung injury in polymorphonuclear leukocyte (PMN)-depleted mice. Sham, mice aspirated with saline. PMN depletion reduced lung permeability index (PI) after acid aspiration by 59% compared with PMN-replete mice (*P < 0.05).
[View Larger Version of this Image (9K GIF file)]

Fig. 3. Acid aspiration-induced lung injury after complement inhibition and PMN depletion. Mice genetically deficient in C3 [C3 knockout (ko)] had a 58% reduction, and mice treated with soluble complement receptor type 1 (sCR1) had a 54% reduction in lung PI after acid aspiration compared with wild-type littermates (* P < 0.05). C4-deficient mice (C4 ko) were not protected from acid injury. Mice depleted of PMNs and treated with sCR1 had an 85% reduction in lung PI (dagger  P < 0.05 compared with sCR1-treated animals).
[View Larger Version of this Image (13K GIF file)]

Table  1.   Acid aspiration-induced lung injury in selectin-deficient mice
Type of Mouse n Aspirate Lung PI
E-selectin knockout 20 Acid 2.61 ± 0.10 
E-selectin wild-type 13 Acid 2.64 ± 0.10 
P-selectin knockout 14 Acid 2.48 ± 0.10 
P-selectin wild-type 12 Acid 2.35 ± 0.14 
Wild-type (sham)  9 Saline 1.60 ± 0.02*
Values are means ± SE; n, no. of animals. PI, permeability index. * P < 0.05 compared with all other groups.

RESULTS

Instillation of 0.1 N HCl into the trachea of mice resulted in a pulmonary injury described by the extravasation of 125I-albumin into the interstitial and alveolar spaces. Acid aspiration (n = 10) resulted in a lung PI of 3.24 ± 0.31, significantly elevated compared with the PI of saline-aspirated (sham) animals (1.55 ± 0.05; n = 13, P < 0.05) (Fig. 2). The circulating neutrophil count did not significantly change during the aspiration protocol, with a mean absolute neutrophil count of 995 ± 113 cells/µl before and 1,395 ± 102 cells/µl 4 h after aspiration.

PMN-depleted mice. After acid aspiration, neutropenic mice (n = 11) with a mean absolute PMN count of 141 ± 43 cells/µl had a reduced lung PI of 2.25 ± 0.15 compared with acid-aspirated, neutrophil-sufficient mice, with a PI of 3.24 ± 0.31 (n = 10, P < 0.05) (Fig. 2). Serum C3 levels in PMN-depleted mice were not different from control animals, indicating that immunoneutralization of neutrophils did not activate C (data not shown).

P- or E-selectin-deficient mice. Acid aspiration in P-selectin-knockout mice (n = 14) led to a lung PI of 2.48 ± 0.10, which was not significantly lower than that in the wild-type acid-aspirated control mice with a lung PI of 2.35 ± 0.14 (n = 12). Similarly, E-selectin-knockout mice (n = 20) were not protected from acid injury with a PI of 2.61 ± 0.10 that was not reduced compared with wild-type acid-aspirated control mice with a lung PI of 2.64 ± 0.10 (n = 13). Littermates undergoing sham aspiration with instillation of 0.9% saline into the distal airways (n = 9) had a lung PI of 1.60 ± 0.02 (Table 1). The injury after acid aspiration in the P- and E-selectin wild-type groups was lower than that seen in the other control groups. This is presumably because of the different genetic backgrounds and is the reason for using specific wild-type controls for each experiment.

C-deficient and sCR1-treated mice. Inhibition of both alternative and classic pathway C activation was accomplished in mice by intravenous sCR1 before the instillation of acid. sCR1-treated mice (n = 12) had a lung PI of 2.32 ± 0.09, which is significantly reduced compared with that of C-sufficient mice (n = 23) with a lung PI of 3.22 ± 0.27 (P < 0.05). Similarly, mice genetically deficient in C3 (n = 10) were protected from acid aspiration with a lung PI of 2.26 ± 0.12 (P < 0.05), whereas C4-deficient mice (n = 10) had a lung PI of 3.18 ± 0.17 (not significant) (Fig. 3). In this set of experiments, saline-aspirated sham animals (n = 13) had a lung PI of 1.55 ± 0.05.

C inhibition in neutrophil-depleted mice. To test for additive effects of C and neutrophils, a group (n = 5) of neutropenic mice (mean absolute PMN count of 140 ± 72 cells/µl) was treated with sCR1 before aspiration (Fig. 3). This combined-treatment group had a reduced lung PI of 1.86 ± 0.029 (P = 0.008 compared with sCR1 alone-treated animals but only P = 0.100 compared with PMN-depleted animals).

C3 immunostaining. Lungs snap-frozen in optimal cutting-temperature compound 4 h after acid aspiration were stained for C3. C3 was localized on injured alveoli in acid-aspirated lungs (Fig. 4A). C3 was restricted to intravascular spaces in sham, saline-aspirated lungs (Fig. 4B).
Fig. 4. C3 immunostaining of injured alveoli. Immunostaining reveals C3 deposition on alveoli and fibrinous exudates in acid-aspirated lungs (A). C3 immunoreactivity is restricted to intravascular spaces in lungs from sham mice (B). No nonspecific labeling is seen with control immunoglobulin G (C). Magnification, ×100.
[View Larger Version of this Image (81K GIF file)]

DISCUSSION

This study examines the role of inflammatory mediators in acid aspiration lung injury. Because aspirated acid is rapidly neutralized by pulmonary secretions, to account for the observations that the damage intensifies over the subsequent 4 h, additional injurious mediators are postulated to be operative. The initial, direct tissue injury is amplified by an inflammatory reaction. We studied two components of this reaction, neutrophils and C.

Neutropenic mice had a 59% reduction in lung injury after acid aspiration. This confirms similar results reported in other species (9-11). Previous studies in the rat have shown that locally produced leukotriene B4 and thromboxane A2 recruit and activate neutrophils. Inhibiting eicosanoid synthesis by lavage with antagonists inhibited the influx of neutrophils (9). Other reports indicate that interleukin-8 (IL-8) levels rise in rabbit lung lavage fluid after acid aspiration. Immunoneutralization of this chemokine attenuates PMN sequestration and lung injury (5). Thus acid injury appears to stimulate eicosanoid and IL-8 release, likely from airway epithelial cells, alveolar epithelial cells, and/or alveolar macrophages. Recruited and activated PMNs release peroxides (26) and proteases (14), providing a mechanism by which to injure the endothelial and epithelial barrier, thereby allowing passage of protein-rich fluid into the interstitial and alveolar spaces.

PMNs interact with endothelial cells in an orderly and sequential fashion via adhesion molecules (20). The selectin family of cell surface proteins is thought to be responsible for the initial tethering of neutrophils in the microvessels. P-selectin, contained in Weibel-Palade bodies, is rapidly expressed on endothelial plasma membranes after contact with chemoactivators (6, 13). E-selectin requires gene expression and appears on endothelial cells several hours after exposure to inflammatory cytokines such as IL-1 or tumor necrosis factor-alpha (2). L-selectin is constitutively expressed on leukocytes and is rapidly shed on their activation (23). Each selectin binds to a glycoprotein counterreceptor expressing sialylated Lewis X-related oligosaccharides, such as P-selectin glycoprotein ligand-1 (19). After initial selectin interaction, it is generally accepted that rolling PMNs become firmly attached to endothelium via the integrin family of adhesion molecules (3), whereby the beta 2-integrins bind to endothelial intercellular adhesion molecule 1 and 2, part of the Ig superfamily.

The operative adhesion molecule after acid aspiration was speculated to be a selectin because studies have shown that anti-beta 2-integrin therapy (immunoneutralization of CD18) did not affect either neutrophil sequestration or lung injury (4, 5, 9-11). We used selectin-deficient mice to determine the role of this adhesion molecule in acid aspiration injury. Surprisingly, neither P- nor E-selectin alone played an indispensable role in our murine aspiration model. To exclude an overlapping function of the selectin adhesion molecules, double knockouts could be employed (21).

The mechanism by which neutrophils become sequestered in acid-aspirated lungs is not clear. It does not appear to involve the selectin or beta 2-integrin (4, 5, 9-11) family of adhesion molecules. Mechanical entrapment of circulating platelet-neutrophil or neutrophil-neutrophil aggregates in lung microvasculature is unlikely because aggregation requires selectin and/or integrin adhesion molecules. Another possible mechanism of entrapment involves elevated local concentrations of leukotriene B4, thromboxane A2, or IL-8 (5, 9-11), agents that may change PMN deformability, leading to their entrapment and activation in the pulmonary capillaries (16).

C activation, as well as PMN activation, can lead to self-destructive tissue injury. Previous reports have shown that the C inhibitor sCR1 reduced acid aspiration lung injury (18). In the present study, acid aspiration in C3 and C4 knockout mice was performed to determine the extent and pathway of C activation. C3-deficient animals, unable to activate C3 and subsequent C components via either pathway, were protected from injury (58%) to the same degree as animals treated with the C inhibitor sCR1 (54%). In contrast, C4-deficient animals, which are unable to activate C3 via the classic pathway but have an intact alternative activation pathway, were not protected from injury. These data lead us to conclude that the effect of sCR1 is due to inhibition of C3 activation and that C inhibition is as potent as PMN depletion in reducing lung injury. Also, C activation occurs via the alternative pathway. The interaction of C with lung tissue that produces C activation may be via an altered cell membrane or loss of membrane C regulatory proteins (22). With regard to the latter, acid exposure may cause loss of these normal protective mechanisms and thereby promote C activation. Indeed, we find C3 deposition on alveolae in mice aspirated with acid but not on those of mice aspirated with saline. These results are in contrast to other forms of inflammatory injury such as that after skeletal muscle ischemia. During reperfusion of hindlimb muscle, C is activated via the classic pathway (24). IgM is deposited on injured tissue, leading to the conclusion that ischemia results in altered cell immunogenicity, IgM binding, and subsequent C activation.

Local C activation may injure tissue by multiple independent mechanisms. First, the activation products C3a and C5a act as chemotaxins, stimulating the migration of leukocytes to the C-activation sites and upregulating cell adhesion molecules (2). Second, cell-bound C fragments such as iC3b act as adhesion counterreceptors and chemoactivators, signaling oxidative metabolism in neutrophils. Thus Rabinovici (18) found lung leukosequestration without injury in animals treated with C inhibitors, suggesting the importance of the second mechanism of action. Third, C activation can directly damage cells by formation of the membrane attack complex (C5b-9), which is a porelike structure that inserts itself into plasma membranes and allows indiscriminate movement of water and ions such as calcium. This results in a membrane perturbation, resulting in second messenger signaling, enzyme activation, and possible osmotic lysis (12). To study whether C acts through PMN recruitment/activation or independently by direct injury to cells, we inhibited C activation with sCR1 in neutropenic mice. These animals had an 85% reduction in lung permeability, significantly better than the 54% reduction seen by using single therapy with sCR1, indicating an effector role for neutrophils.

This study describes a novel mouse model of acid aspiration that uses extravasation of intravenous albumin as the primary marker of injury. This model is advantageous in its ability to utilize genetically altered animals to study inflammatory cascades. However, the model has obvious limitations because of animal size because it is not possible with present technology to draw serial blood samples for pulmonary physiological studies or to measure airway dynamics.

In conclusion, acid aspiration results in an inflammatory injury. Neutrophil depletion reduced the injury by 59%. Neither P- nor E-selectin-deficient animals were protected from injury. Inhibiting C activation with sCR1 reduced injury by 54%, similar to the protection seen in C3 knockout mice. C4 knockout mice, however, were not protected from injury, indicating that C activation occurs via the alternative pathway. Neutropenic animals treated with sCR1 had an 85% reduction in injury.

ACKNOWLEDGEMENTS

The authors thank D. Smith and R. A. Mercier for valuable help with the surgical preparations and A. C. Imrick for performing the immunohistochemistry.

FOOTNOTES

   This work was supported in part by National Institutes of Health Grants GM-52585-01, GM-35141-09, GM-07560-18, AI-32544-03, and HD-17461; an Arthritis Foundation Biomedical Science grant, The Brigham Surgical Group, Inc.; and The Trauma Research Foundation.

Address for reprint requests: H. B. Hechtman, Brigham and Women's Hospital, 75 Francis St., Boston, MA 02115.

Received 12 November 1996; accepted in final form 16 May 1997.

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