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Anesth Analg 2004;98:1273-1279 © 2004 International Anesthesia Research Society doi: 10.1213/01.ANE.0000111111.76779.B3
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Abstract |
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Our aim in the current study was to determine whether recombinant surfactant protein-C (rSP-C) surfactant improves acute lung injury (ALI) induced by intratracheal acidified milk products. Twenty-eight rabbits were randomly divided into four groups. ALI was induced with intratracheal acidified infant formula (0.8 mL/kg, pH 1.8) in 3 groups. The control group received intratracheal acidified saline. Therapy groups received 1 of 2 doses of intratracheal rSP-C surfactant (0.5 or 2 SP-C mg/kg) 30 min after the acidified infant formula. The lungs were ventilated with 100% oxygen for 4 h after induction of ALI. Acidified infant formula dramatically reduced oxygenation and lung compliance, and increased resistance. Both doses of rSP-C improved the variables [mean PaO2 (mm Hg) and compliance (mL/cm H2O) at 4 h: 61 and 0.4 for infant formula, 162 and 1.0 for small-dose rSP-C, and 152 and 1.2 for large-dose rSP-C, respectively; P < 0.05]. Pulmonary leukosequestration and edema, and severe morphological changes were attenuated by rSP-C treatment (ALI score: 14, 7, 7 in infant formula, small-dose rSP-C, and large-dose rSP-C; P < 0.05). The efficacy was similar for the two doses of rSP-C. These findings suggest that intratracheal administration of rSP-C ameliorates ALI induced by aspiration of acidified milk products.
IMPLICATIONS: Small or large doses of recombinant surfactant protein-C surfactant given 30 min after intratracheal acidified infant formula attenuated physiological, biochemical, and morphological lung damage.
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Introduction |
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Experimental intratracheal instillation of acidified milk products causes severe acute lung damage (1). From the perspective of pediatric clinical practice, this animal model of acid aspiration-induced lung injury may be clinically more relevant than one using hydrochloric acid alone. The inflammatory/exudative stage of acidified milk product-induced acute lung injury (ALI) occurs in two stages: initial direct physiochemical damage (initial phase) and immune-mediated auto-tissue lung injury (second phase) (2). The initial phase of ALI develops immediately after acid aspiration, and impairment of oxygenation and the increase in permeability reach a peak at 1 h with pathological alterations consisting of alveolar/capillary destruction followed by alveolar hemorrhage and influx of protein-rich edema fluid. The second phase occurs 2–3 h after acid aspiration with the peak of lung injury seen 4 h postaspiration. This late phase is consistent with an acute inflammatory response mediated mainly by neutrophils.
Accumulation of neutrophils into the lung is promoted by chemotaxins including interleukin-8 (IL-8) and thromboxane B2 (TxB2). Activated neutrophils can impair surfactant function by releasing reactive oxygen species (3). Morphological changes are characterized by edema accompanied by intraalveolar hemorrhage, alveolar infiltration of neutrophils, fibrin formation, and necrosis of lung parenchymal cells, similar to the pathology observed in acute respiratory distress syndrome (ARDS). The intraalveolar blood components and plasma exudates also inhibit surfactant function (4), leading to atelectasis and a mismatch of the ventilation-perfusion ratio. Furthermore, the acidified milk products directly damage type II pneumocytes, resulting in impairment of surfactant production. We previously demonstrated that a modified bovine surfactant preparation (Surfacten®) improved pulmonary function and gas exchange, and diminished lung morphological changes in our ALI model (5). However, the high cost of this drug often prevents its use in clinical settings. Another surfactant, containing recombinant human surfactant protein-C (rSP-C) (Venticute®; ALTANA Pharma, Konstanz, Germany) was recently developed. SP-C is a hydrophobic protein with a molecular weight of 4 kD which reduces surface tension at the air-alveolar interface (6). The rSP-C surfactant has been proven to physiologically and morphologically improve ALI induced by repetitive lung lavage (7) and to be as effective as bovine-derived surfactants in an animal model (8). Thus, we conducted the current study to examine whether rSP-C surfactant can improve oxygenation and lung mechanics, and repair pathological damage induced by an acidified infant formula. The observation of our study lasted for 4 h after acid instillation because during this period, lung injury in the second phase is more prominent than the initial pulmonary changes.
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Methods |
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The current study was approved by the animal care review board of Kobe University Graduate School of Medicine. The care and handling of the animals were in accordance with the National Institutes of Health guidelines. We used 28 male Japanese White rabbits (body weight, 2.0–2.4 kg) which were anesthetized with 60 mg/kg ketamine given IM and intubated with an endotracheal tube through a tracheotomy. A catheter was inserted into a left ear vein for infusion of fluids. Anesthesia was maintained with infusion of ketamine at a rate of 30 mg · kg–1 · h–1 and IM xylazine 8 mg/kg hourly. An arterial catheter was placed through a cutdown in the right femoral artery to monitor mean arterial blood pressure and take samples for blood gas analysis and peripheral leukocyte count. The lungs were ventilated with an infant ventilator (IV100B; Sechrist, Anaheim, CA) with an inspired oxygen concentration of 100%. The tidal volume was initially set to 10 mL/kg after which 2 cm H2O of positive end-expiratory pressure (PEEP) was added as also used in our previous study using Surfacten® (5). The respiratory rate was controlled to produce an initial PaCO2 of 31–38 mm Hg. The animals were placed supine on a heating pad under a radiant heat lamp to keep orally measured body temperature between 37.6° and 39.1°C. Heart rate was continuously monitored with an electrocardiograph. Central venous pressure was also monitored via a catheter inserted through the right jugular vein. Lactated Ringer’s solution was administered IV at a rate of 8 mL · kg–1 · h–1. The blood withdrawn (1 mL/time) was replaced with a bolus administration of lactated Ringer’s solution (2 mL).
The rSP-C surfactant (Venticute®) contains 2% rSP-C in phospholipids (PL; dipalmitoylphosphatidylcholine and palmitoyloleoyl-phosphatidylglycerol in a 70:30 [wt/wt] ratio), plus 5% palmitic acid (9). The rSP-C surfactant was suspended in normal saline to achieve a concentration of 40 mg PL/mL (=0.8 mg rSP-C/mL). SP-B deficiency has been shown to cause respiratory failure in adult mice (10), whereas reduced SP-B is associated with accumulation of misprocessed SP-C, probably leading to respiratory failure (10). The experiments of Häfner et al. (7) clearly demonstrate that the rSP-C surfactant (Venticute®) used in our study is at least covalent to Alveofact® (1.7% SP-B) in achieving full oxygenation as well as in reverting the hyaline membrane formation in a rat lung lavage model of ARDS. This leads us to assume that SP-B is not mandatory to achieve the biophysical properties of surfactant needed for the treatment of diseases such as ARDS.
The animals were randomly divided into four groups by using the sealed-envelope technique. ALI was induced by intratracheal administration of acidified infant formula (0.8 mL/kg, pH 1.8; Sukoyaka®, Yukijirushi, Sapporo, Japan) in 3 groups (infant formula, small-dose rSP-C, and large-dose rSP-C groups). The control group received intratracheal acidified saline (0.8 mL/kg, pH 1.8; acidified saline group). The acidified solutions were titrated to a pH level of 1.8 by the addition of 6 N HCl using a pH meter (Horiba F-8L®; Horiba, Kyoto, Japan), which has a 0.01 pH units precision over the entire pH range. The electrode was calibrated using standard buffers at pH values of 1 and 4. The acidified milk product was instilled and followed by manual bagging for 2 min. Therapy groups received 1 of 2 doses of intratracheal rSP-C surfactant (25 or 100 mg PL/kg = 0.5 or 2 rSP-C mg/kg) 30 min after the acidified infant formula. The dose of rSP-C surfactant used in the current study was based on several previous experiments (8,11). The timing of rSP-C surfactant administration (30 min after instillation of acidified infant formula) after evidence of gastric aspiration is clinically feasible in a hospital setting. The volume of the drug suspension was 0.625 mL/kg for the small-dose rSP-C group and 2.5 mL/kg for the large-dose rSP-C group. This volume was divided into two aliquots for each lung. To obtain optimal distribution, the rSP-C surfactant was instilled into the trachea of rabbits in left and right positions with head-up and head-down tilt. This procedure is the same as that used clinically for infants with respiratory failure. The acidified saline group did not receive rSP-C surfactant.
Hemodynamics, lung compliance and resistance, arterial gas analysis results, and peripheral leukocyte and platelet counts were recorded at specified points. Arterial blood gases were analyzed with a blood gas analyzer (ABL2; Radiometer, Copenhagen, Denmark), and the number of leukocytes was measured with an automated blood cell counter (Sysmex K-1000; Sysmex, Kobe, Japan). Lung mechanics were measured in triplicate each time with the passive expiratory flow-volume technique. The air flow was measured with a Flemish 00 pneumotachograph and a differential pressure transducer (model MP045; Validyne Engineering, Northbridge, CA). Airway pressure was measured at the proximal end of the pneumotachometer with a semiconductor pressure transducer (model P-300 501G; Copal Electronics, Tokyo, Japan). The volume of each breath was determined by digital integration of the air flow using a respiration monitor (Aivision, Tokyo, Japan). The compliance and resistance of the total respiratory system were then calculated on a personal computer. Our preliminary experiment revealed that the coefficient of variation for the measurement system of the lung mechanics was 2%–5%, indicating that this was a reliable and reproducible method.
After blood sampling for chemiluminescence, the heart and lungs were removed en bloc by an observer blinded to the nature of the experiments. The left upper lobe of each lung was weighed and then dried to constant weight at 60°C for 24 h in an oven. The W/D weight ratio of the lungs was calculated to assess tissue edema.
Through the right mainstem bronchus, 35 mL of saline with EDTA-2Na at 4°C was slowly infused and withdrawn to obtain BAL fluid. This procedure was repeated three times. Indomethacin was added to the BAL fluid to inhibit the further metabolism of arachidonic acid to prostaglandins during analysis. The BAL fluid was then analyzed for cell count and cell differentiation. A cytocentrifuged preparation (Cytospin 2; Shandon Southern Products, Pittsburgh, PA) of the BAL fluid was stained with Diff-Quick® (Harleco, Gibbstown, NJ) for cell differentiation. The cells contained in the fluid were counted with a Bürker-Türk hemocytometer. The fluid was centrifuged at 250g at 4°C for 10 min to remove the cells, after which the cell-free supernatant was divided into several aliquots and stored at –80°C until assay. The substances and mediators that were measured in the BAL fluid comprised albumin concentrations, determined by nephelometry with the immunoglobulin G fraction of goat anti-rabbit albumin (Cappel, Durham, NC); concentrations of leukotriene B4, measured by enzymeimmunoassay (Amersham-Pharmacia, Buckinghamshire, UK); and concentrations of thromboxane A2 (TxA2) and prostacyclin, quantified by radioimmunoassay kit (NEN, Boston, MA, and Amersham) in the form of 11-dehydro-TXB2 (11-DTxB2) and 6-keto-prostacyclin F1
, their respective stable metabolites. In addition, activated complement protein 3 levels were determined by radioimmunoassay kit (Amersham), and concentrations of IL-8 were determined with a human enzyme immunoassay kit (Amersham) that cross-reacts to rabbit IL-8 by using recombinant rabbit IL-8 for the standard concentration curve (12).
Immediately after the rabbits had been killed, the left lower lobe was fixed by instillation of 10% formaldehyde solution at 20 cm H2O. The specimens were embedded in paraffin wax, stained with hematoxylin and eosin, and examined under a light microscope. The ALI was scored by the same blinded observer on the basis of 4 factors: 1) alveolar congestion, 2) hemorrhage, 3) infiltration or aggregation of neutrophils in air space or vessel wall, and 4) thickness of alveolar wall/hyaline membrane formation. Each factor was graded on a 5-point scale: 0 = minimal damage, 1+ = mild damage, 2+ = moderate damage, 3+ = severe damage, and 4+ = maximal damage. Thus, the minimum score was 0, and the maximum score 16.
Seven microscopic images were obtained from each tissue sample with an ACT-1 (Nikon, Tokyo, Japan) and the area of the alveolar space was morphologically determined with image analysis software (WinRoof; Mitani, Tokyo, Japan), whereas alveolar size was expressed as the ratio of the alveolar over the parenchymal area. The number of alveolar and interstitial lung neutrophils was morphometrically determined by two blinded observers. Each slice was observed under the light microscope at x100 magnification (visual field: 372 x 264 µm2) to count neutrophils in 10 randomly chosen fields. The neutrophil count is expressed as the number of neutrophils per square centimeter of tissue.
The ALI score data are shown as medians, whereas the other data are expressed as mean ± SD. Repeated-measures data (i.e., oxygenation, lung mechanics, peripheral leukocytes and platelets, and hemodynamics) were statistically analyzed with the repeated-measures analysis of variance. The data for BAL fluid, W/D weight ratio, microscopic neutrophils count, and alveolar size were analyzed by one-way analysis of variance followed by the Tukey-Kramer post hoc test. The ALI scores were analyzed with the Kruskal-Wallis rank test followed by the Dunnett test. P < 0.05 was deemed statistically significant.
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Results |
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There was no difference in mean arterial blood pressure, heart rate, or central venous pressure among the groups (Table 1). Peripheral circulating leukocytes gradually decreased after administration of intratracheal acidified infant formula (Table 1). Leukopenia was less severe in rabbits receiving rSP-C surfactant although not significantly so (Table 1).
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Oxygenation was dramatically reduced after intratracheal acidified infant formula and remained low during the study period. The reduction in oxygenation was diminished by either dose of rSP-C surfactant with a similar effect (Fig. 1). Lung compliance dramatically decreased and lung resistance increased after induction of ALI. Either dose of rSP-C surfactant then decreased the lung injury and improved lung mechanics to a similar extent (Fig. 1). The slight reduction of oxygenation and lung compliance in the control group was probably attributable to the instillation of acidified saline.
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Recovery rates of BAL fluid in the groups ranged from 71% to 78%, thus showing no significant differences among the groups. Both doses of rSP-C attenuated the increase of leukocytes in the BAL fluid observed in rabbits receiving acidified infant formula (Table 2). The increase of the ratio of neutrophils to total leukocytes (%neutrophils) was less pronounced in the rSP-C treatment groups (Table 2). BAL fluid concentrations of albumin were larger in rabbits receiving acidified infant formula than in those receiving acidified saline (Fig. 2), whereas this increase in albumin concentrations was diminished in rabbits treated with rSP-C surfactant. Acidified infant formula increased the lung W/D weight ratio, and this increase was attenuated by both doses of rSP-C surfactant to a significant and similar degree (Fig. 2). Acidified infant formula alone significantly increased IL-8, activated complement protein 3, and 11-DTxB2 levels in BAL fluid, whereas a small dose of rSP-C surfactant significantly reduced BAL fluid concentrations of IL-8 and 11-DTxB2 (Table 2).
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Light microscopic findings for the rabbits given acidified infant formula alone included extensive morphological lung damage consisting of edema, hemorrhage, ruptured and thickened alveolar walls, infiltration of inflammatory cells in alveolar and interstitial spaces, diffuse proteinaceous exudate, and hyaline membrane formation. These injuries were less severe in the rSP-C-treated groups (Fig. 3). The ALI score was reduced by rSP-C surfactant, and the neutrophils in alveolar and interstitial spaces were reduced by both doses of rSP-C surfactant (Table 2). Finally, the aerated alveolar area was larger in the rabbits receiving rSP-C surfactant than in those receiving acidified infant formula alone (Table 2).
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Discussion |
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Intraalveolar plasma exudates and protein-rich edema fluid inhibit surfactant activity (4). Although surfactant activity was not measured directly in our study, we were able to show that lung compliance was reduced in rSP-C-treated rabbits. Surfactant dysfunction increases surface tension on the alveolar wall and subsequently causes atelectasis. This functional surfactant deficiency leads to further accumulation of edema fluid in the alveolar spaces because of the increase in retractive forces across the alveolar-capillary membrane. Shear forces generated during repetitive opening and closing of atelectatic lung units increase production of cytokines leading to exacerbation of lung injury (13). Treatment with rSP-C may reduce cytokine production through the mechanism mediated by shear stress. In addition to activation of fibroproliferation, activation of transforming growth factor-ß, a multifunctional cytokine, is thought to be important in the early stages of ALI (14). Transforming growth factor-ß regulates surfactant homeostasis through reducing mRNA expression of surfactant protein (15,16). Tumor necrosis factor-
, an inflammatory cytokine, also reduces SP-C gene expression within 12 hours after stimulation (17). Use of exogenous rSP-C surfactant may thus help maintain the correct surfactant homeostasis during the inflammatory and fibroproliferative stages. Long-term studies are required to test this hypothesis, however, because our study covered only four hours. The result of our study showed that peripheral leukopenia and lung leukosequestration were less prominent in the rSP-C surfactant-treated rabbits. Surfactant has suppresses the production of several proinflammatory cytokines in alveolar macrophages (18). Similarly, the PL of surfactant inhibits TxB2 release (19). The rSP-C surfactant decreased IL-8 and TxB2 levels in the alveolar fluid, although not significantly, in large-dose rSP-C. In in vitro experiments, surfactant and liposomes of dipalmitoylphosphatidylcholine inhibit adherence of human neutrophils (20), and may also contribute to the suppressive effect of rSP-C surfactant on lung leukosequestration. Recruitment of neutrophils to the lung can also be explained by differences in the alveolar volume, with more physical trapping of neutrophils occurring in collapsed lung units as evidenced by morphological changes.
Because the initial damage occurs within 10 minutes after aspiration of the milk products, the use of rSP-C surfactant 30 minutes after the aspiration can theoretically not prevent the direct nonimmune-mediated injury. However, surfactant has been reported to inhibit superoxide production from neutrophils and alveolar macrophages (21). This effect may be attributed, in part, to suppression of protein kinase C activation (22). In the current study, pulmonary edema (assessed with the W/D weight ratio) associated with endothelial/epithelial hyperpermeability (assessed in terms of BAL albumin) was less in rabbits receiving rSP-C surfactant. This suggests that treatment with rSP-C surfactant lessened the secondary epithelial-capillary membrane damage mediated by the neutrophils’ mechanism and consequently attenuated progression of lung edema, even though superoxide production itself was not measured in our study. Surfactant also regulates fluid balance in interstitial and alveolar spaces (23). Attenuation of lung edema formation by rSP-C surfactant may thus be ascribed to this mechanism.
In a previous study (8), the action of rSP-C-containing surfactant preparation was found to be similar to that of bovine-derived surfactants in a rat lung lavage model of ARDS. The lung lavage model is totally deficient in surfactant, unlike the acidified milk-induced ALI which is a relatively surfactant-deficient model because of the large amount of surfactant inhibitors. In experimental ARDS, the effect of surfactant replacement depends on the type of animal model and the degree of lung injury present at the time of therapy (24). It would therefore be worthwhile to assess the effectiveness of rSP-C for ARDS models other than that produced by lung lavage. Furthermore, we need additional studies to compare the efficacy of rSP-C surfactant and bovine-derived surfactants in our ALI model. No dose-dependent effect of rSP-C surfactant was observed in the current study, in contrast to the findings of previous reports (8) using a rat lung lavage-induced ALI model. These discrepant results are probably attributable to differences in ALI model and species, whereas the improvement effected by the large dose of rSP-C surfactant may have been offset by the larger amount of saline used as a carrier. Furthermore, the less than complete improvement of oxygenation and lung mechanics attained with rSP-C surfactant in the current study may be attributed to continuing progression of the disease as well as the possibly heterogeneous distribution of rSP-C. Intratracheal infusion of the drug may have resulted in more homogeneous distribution.
Because an adequate PEEP level during administration of surfactant is essential for uniform distribution, the PEEP level (2 cm H2O) used in the current study may have been insufficient. Furthermore, a ventilation strategy using moderate levels of PEEP is generally desirable, particularly for uniform distribution of exogenous surfactant. Alternatively, the less than satisfactory physiological improvements obtained with rSP-C surfactant may be explained by dilution-induced loss of surface activity in the underlying edematous lung. To overcome this problem, repeated doses of rSP-C surfactant may be necessary. Dexamethasone and phosphodiesterase-IV inhibitors, which have an antiinflammatory effect, have been shown to enhance the efficacy of rSP-C surfactant in oxygenation and hyaline membrane formation of lung lavage-induced ALI (11,25). Further studies are needed to assess the effects of the addition of glucocorticosteroids or phosphodiesterase-IV inhibitors in our ALI model. We are thus unable to extrapolate our observations directly to other ALI experimental models (e.g., using endotoxin or oleic acid), and other delivery techniques. Nebulized rSP-C surfactant may be less effective than instillation of the drug, because obstruction of small peripheral airways by the infant formula itself may have impeded access of aerosolized rSP-C surfactant to the alveoli in our ALI model. The beneficial effects of rSP-C surfactant may be enhanced by first removing the milk product and surfactant inhibitors (plasma exudates and edema fluids) from airways and alveoli by means of the tracheobronchial lavage with diluted rSP-C surfactant suspension.
The current study includes several limitations. First, the longevity of pathological and physiological improvements attained with rSP-C, as well as the need for additional doses, remains unclear because the ALI model was followed up for only four hours. Second, the lack of a dose-response relationship is odd, therefore the response needs additional examination and characterization. Finally, it is unclear if the improvements in lung mechanics will indeed translate into an improvement in clinical outcomes and a decrease in mortality.
In conclusion, we have shown that intratracheal posttreatment with rSP-C surfactant (25 and 100 mg PL/kg) attenuated the magnitude of physiological and histological lung damage induced by acidified infant formula. Improvement in the lung injury was similar for the 2 doses. The current study may form the basis for a clinical trial to clarify whether the use of exogenous rSP-C surfactant can be a therapeutic approach for pediatric patients with ALI induced by aspiration of milk products.
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Acknowledgments |
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Support was provided solely from departmental source.
We would like to express our gratitude to ALTANA Pharma for the generous supply of rSP-C surfactant.
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References |
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