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1 Division for Experimental
Perinatal Pathology, Karolinska Hospital, S-171 76 Stockholm,
Sweden; 2 Department of Molecular
Pathology, ABSTRACT Grossmann, Gertie, Yasuhiro Suzuki, Bengt Robertson, Tsutomu
Kobayashi, Per Berggren, Wen-Zhi Li, Guo-Wei Song, and Bo Sun.
Pathophysiology of neonatal lung injury induced by monoclonal antibody to surfactant protein B. J. Appl.
Physiol. 82(6): 2003-2010, 1997.
animals, newborn; electron microscopy; lung compliance; lung
permeability; respiratory insufficiency
INTRODUCTION RAPID ADSORPTION of surface-active material to the
air-liquid interfaces of the lung is of vital importance for the first breath and subsequent neonatal adaptation. To meet this requirement, the pulmonary fluid of the normal full-term neonate contains large amounts of surfactant lipids associated with at least three specific proteins, currently known as surfactant proteins A (SP-A, 28-36 kDa, hydrophilic), B (SP-B, 8.7 kDa, hydrophobic), and C (SP-C, 4.2 kDa, palmitoylated and ex- tremely hydrophobic) (for
review, see Ref. 7). SP-A and probably also SP-B are essential for conversion of newly secreted lamellar bodies to tubular
myelin (19, 21), an intermediate phase required for adsorption of endogenous surfactant at the alveolar air-liquid interfaces.
In experiments on ventilated immature newborn rabbits, we have shown
that exogenous natural surfactant (containing all 3 surfactant-associated proteins mentioned above) loses its therapeutic
effect when incubated with a monoclonal antibody to SP-B, whereas a
monoclonal antibody to SP-A had no such effects (10). In a study on
near-term newborn rabbits we also demonstrated that blocking of
endogenous SP-B with a cross-reacting monoclonal antibody (raised
against porcine SP-B) leads to severe respiratory failure associated
with exudative and inflammatory lung lesions, including hyaline
membranes. We speculated that the disturbance of lung function
developing shortly after tracheal instillation of the antibody was in
part mediated by inactivation of surfactant but probably also involved
other mechanisms.
The present experiments were designed to further clarify the
pathophysiology of this new animal model of neonatal lung disease. Studies were performed in near-term newborn rabbits using a monoclonal antibody raised to rabbit SP-B, and the morphological evolution of lung
injury was characterized in animals examined at various times after
instillation of the antibody. We also quantified recruitment of
inflammatory cells to the air spaces and determined
vascular-to-alveolar protein leakage during the course of the disease.
METHODS Isolation and Characterization of the Monoclonal Antibody
Near-term
newborn rabbits were exposed via the airways to a monoclonal antibody
to surfactant protein B and ventilated for 0-120 min. Control
animals received nonspecific rabbit or mouse immunoglobulin G, saline,
or no material via the airways. Administration of the antibody at 
40
mg/kg elicited an immediate, significant fall in lung-thorax compliance
associated with progressive intra-alveolar edema and/or
alveolar collapse and necrosis and desquamation of airway epithelium,
and hyaline membranes. The vascular-to-alveolar leak of human albumin
and human immunoglobulin G, injected intravenously at birth and
determined in lung lavage fluid 60-120 min after instillation of
the antibody, was 1.8% for the left lung, with no difference between
the markers. The average leak in control animals ventilated for 120 min
was <0.3% (P < 0.05). Cytospin preparations of lung lavage fluid from animals exposed to the antibody
showed significantly increased recruitment of neutrophilic granulocytes. The pathology and pathophysiology of neonatal lung injury
induced by the monoclonal antibody to surfactant protein B probably
reflect a combination of direct inactivation of surfactant and an
inflammatory response triggered by the immune reaction.
In Vitro Evaluation of Surfactant Inhibition
Rabbit natural surfactant, isolated as described by Frosolono et al. (4), was suspended in normal saline at a phospholipid concentration of 10 mg/ml and incubated with various concentrations of the monoclonal antibody ranging from 0 to 16 mg/ml. Control samples were mixed with nonspecific rabbit or mouse immunoglobulin G (IgG) (Sigma Chemical, St. Louis, MO) at a concentration of 16 mg/ml. The mixtures were kept at room temperature for at least 1 h before evaluation of surface properties at 37°C with a pulsating bubble surfactometer (Electronetics, Amherst, NY). Before onset of pulsation, surface tension was measured over 10 s under static conditions. Adsorption time was defined as the interval from the moment the bubble was made until surface tension had dropped to 30 mN/m. Maximum and minimum surface tension were then recorded under dynamic conditions after 5 min of pulsation, during which surface area of the bubble was compressed by 50% at a rate of 40 cycles/min.Animal Experiments
Experiments were carried out on a total of 112 newborn rabbits obtained from 27 does by hysterotomy at a gestational age of 29.5 days, i.e., ~2 days before full term. At this stage of fetal development, adequate amounts of surfactant have usually accumulated in the alveolar spaces and the lungs are therefore easily ventilated at birth (11).Three series of experiments were performed to evaluate 1) evolution of lung injury in animals killed at various times after receiving a standard dose of antibody, 2) lung protein leakage during various times after administration of a standard dose of antibody, and 3) recruitment of inflammatory cells to the air spaces after instillation of a standard dose of antibody.
All neonates were weighed, anesthetized with pentobarbital sodium (0.5 mg ip), relaxed with pancuronium bromide (0.02 mg ip), and tracheotomized. The antibody was dissolved in saline at a concentration of 8 mg/ml and administered into the airways via a fine nylon tube at a dose volume of 5 ml/kg. The standard dose of antibody used in our experiments (40 mg/kg) was chosen on the basis of dose-response studies indicating that this amount was required to cause a >45% decrease in lung-thorax compliance in animals ventilated for 120 min (data not shown). The nylon tube was wedged into the tracheal cannula during the instillation procedure to ensure precise dosing. Control animals received nonspecific rabbit or mouse IgG (Sigma Chemical), saline, or no material via the airways. After the instillation maneuver, the neonates were transferred to a system of multiple body plethysmographs, heated to 37°C, and connected in parallel to a common ventilator system delivering 100% oxygen at a frequency of 40 breaths/min and an inspiration-to-expiration ratio of 1:1. Insufflation pressure was individually adjusted to provide a tidal volume of ~10 ml/kg body wt (18). No positive end-expiratory pressure was applied. Tidal volumes were measured with a pneumotachograph connected to the plethysmograph box. Recordings were made every 15 min, and lung-thorax compliance was calculated by dividing tidal volume, expressed as milliliters per kilogram of body weight, with peak insufflation pressure in cmH2O. Electrocardiogram (ECG) was monitored from subcutaneous electrodes. After the scheduled period of artificial ventilation, the animals were killed by intracerebral injection of lidocaine (which causes immediate cardiac arrest). The abdomen was opened, and the diaphragm was inspected for evidence of pneumothorax. Then the chest was opened in the anterior midline, and blood was sampled from the usually bulging right cardiac ventricle for determination of PCO2 and pH. Differences between the protocols for the four series of experiments are outlined below.
Protocol 1. Twenty rabbits from four does were used for protocol 1. Experimental animals receiving the monoclonal antibody (40 mg/kg) were allocated at random to ventilation for 15, 30, 60, or 120 min. Control animals received the same dose of nonspecific rabbit IgG, saline, or no material via the airways and were ventilated for 120 min. Then they were killed, and the lungs were inflated for 30 s with a transpulmonary pressure of 30 cmH2O. This pressure was lowered to 10 cmH2O, which was maintained for 30 min while the lungs were perfused with a mixture of 3.5% formaldehyde and 1% glutaraldehyde at 65 cmH2O. The lungs were embedded in paraffin, and large transverse sections from the lower lobes, stained with hematoxylin and eosin, were examined by conventional light microscopy with particular reference to the alveolar expansion pattern, hemorrhage, desquamation of airway epithelium, and inflammatory and exudative lesions including hyaline membranes. In addition, small pieces from the right upper lobe were sampled for electron microscopy. These tissue blocks were postfixed in 1% osmium tetroxide, dehydrated in graded acetone, and embedded in Vestopal (Bio-Rad, Cambridge, MD). Thin sections stained with lead citrate and uranyl acetate were examined with an electron microscope (model JEM 2000 Ex-II, Jeol, Tokyo, Japan), with particular reference to the structure of type I and type II cells and other components of the alveolar walls and to the presence of tubular myelin in the alveolar spaces. The ultrastructural examination was limited to animals receiving specific antibody and ventilated for 15 or 120 min and to animals treated with saline or nonspecific rabbit IgG and ventilated for 120 min. Protocol 2. These experiments were carried out on 48 newborn rabbits obtained from 11 does. Experimental animals received the monoclonal antibody (40 mg/kg), and control animals received the same amount of nonspecific rabbit IgG, saline, or no material via the tracheal cannula. As markers of lung permeability, we used human albumin (Sigma Chemical; 100 mg/ml) and human IgG (Sigma Chemical; 160 mg/ml). These markers were dissolved together in sterile saline and administered via one jugular vein at a dose volume of 7 ml/kg during the tracheotomy procedure. Animals receiving antibody were randomized to 15, 30, 60, or 120 min of ventilation. Control animals were ventilated for 120 min, with the exception of five nontreated animals, which were killed immediately after injection of the markers to provide baseline values. After the scheduled period of ventilation, the animals were killed, the hilum of the left lung was tied, and the right lung was lavaged with 20 ml/kg of saline. This volume was instilled and withdrawn twice, and the procedure was repeated with fresh saline four times (total lavage volume 100 ml/kg) with an average recovery of 90%. The content of human albumin and human IgG in the lavage fluid was determined by immunodiffusion as previously described (1) and expressed as percentage of injected dose. The left lung was fixed for 24 h by immersion in a mixture of 4% formaldehyde, 6% mercuric chloride, and 1.25% sodium acetate, stored in 70% ethyl alcohol, and embedded in paraffin for immunohistochemical demonstration of human albumin in lung vessels and alveolar spaces. Paraffin sections from the left lung were first incubated with a goat anti-human albumin antibody (A-1151, Sigma Chemical), then with a biotinylated rabbit anti-goat antibody (BA-5000, Vector Laboratories, Burlingame, CA). Subsequent steps included incubation with Vectastain AK-5000 ABC-AP (Vector Laboratories) and visualization of the final reaction product by alkaline phosphatase substrate (kit III Blue SK-5300, Vector Laboratories). Protocol 3. Forty-four neonates from 12 does were used in protocol 3. Experimental animals received the monoclonal antibody (40 mg/kg), and control animals received the same amount of nonspecific rabbit or mouse IgG or no material via the airways. All animals were ventilated for 120 min, except for four nontreated controls, which were killed immediately after the tracheotomy procedure without being ventilated. At the end of the experiment both lungs were washed five times with 40 ml/kg of ice-cold normal saline (total lavage volume 200 ml/kg), with an average recovery of 82%. The cells in the lavage fluid were centrifuged for 10 min at 150 g and 4°C into a pellet, which was resuspended in 1 ml of Türk's solution for microscopic counting of cells in a Bürker chamber. By use of conventional cytospin technique, the remaining cells in the pellet were attached to a glass slide and stained with Giemsa solution for microscopic differential counting of macrophages, lymphocytes, and granulocytes.Statistical Analysis
Data are expressed as means ± SD or, when appropriate, as median and range. Surface tension measurements and data on lung function including protein leakage were subjected to analysis of variance followed by the Student-Newman-Keuls test for differences between groups. Data from cell counts were analyzed with the Mann-Whitney test. P = 0.05 was defined as the limit level for statistical significance.RESULTS
Characterization of the Antibody
The NH2-terminal amino acid sequences of the slower- and faster-migrating protein bands in rabbit surfactant, separated by sodium dodecyl sulfate polyacrylamide gel electrophoresis as described above, were Phe-Pro-Ile-Pro-Leu-Pro- and Phe-Gly-Ile-Pro-X-X-Pro-, respectively. The presence of truncated forms was noted for both proteins, and we concluded that the former corresponded to SP-B and the latter to SP-C.As illustrated in Fig. 1, the antibody
(R48A) showed a strong binding to the band identified as rabbit SP-B
but did not react with rabbit SP-C.
Effect of Antibody on In Vitro Surface Properties of Natural Surfactant
The results of surface tension measurements with the pulsating bubble system are shown in Table 1 and Fig. 2. Adsorption time was prolonged at antibody concentrations8 mg/ml and was >10 s at 16 mg/ml. Values
for maximum and minimum surface tension remained normal at antibody
concentrations between 0 and 0.5 mg/ml and were consistently elevated
at antibody concentrations 4 mg/ml. At an antibody concentration of 1 mg/ml, minimum surface tension remained close to zero, but there was
some elevation of maximum surface tension. Intermediate values for
maximum and minimum surface tension were observed at an antibody
concentration of 2 mg/ml. Nonspecific rabbit and mouse IgG at a
concentration of 16 mg/ml did not interfere with the in vitro surface
properties of natural surfactant.
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max and
min) of natural rabbit
surfactant mixed with different concentrations of monoclonal antibody
to rabbit surfactant protein B (
) or with nonspecific rabbit (
)
or mouse immunoglobulin G (IgG; 
) at 10 mg/ml. Values are median and
range (n = 5-10).
max and
min values recorded in presence
of antibody at >2 mg/ml are significantly larger than those obtained
at lower antibody concentrations (P < 0.01-0.05). max and
min values recorded at an
antibody concentration of 16 mg/ml are significantly higher than those
recorded in presence of rabbit or mouse IgG at the same concentration
(P <0.01).
Data From Animal Experiments
Protocol 1. Nineteen of the 20 animals allocated to protocol 1 survived the scheduled period of artificial ventilation without complications; these animals had a body weight of 41 ± 10 g and a final heart rate of 301 ± 31 beats/min. One animal was excluded from the study because of ECG abnormality (atrioventricular block). Final values for lung-thorax compliance at various times and PCO2 in heart blood in surviving animals are shown in Table 2.
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In animals ventilated for 120 min after instillation of the specific antibody, there was evidence of more advanced injury to type I cells, with necrosis and desquamation leading to direct exposure of interstitial tissue to the alveolar space, which in such areas contained necrotic material (Fig. 3B) corresponding to the alveolar hyaline membranes observed by light microscopy. Some cytoplasmic swelling and mitochondrial vacuolation in type II cells were observed. Many alveolar spaces contained unresorbed fetal lung liquid or edema fluid, and there was also focal intra-alveolar accumulation of electron-dense material, perhaps representing unexpanded lamellar bodies (Fig. 4A). No tubular myelin was identified in the air spaces.
Control animals ventilated for 120 min after receiving saline or nonspecific rabbit IgG showed minimal focal interstitial edema and some swelling of interstitial cells but no other remarkable findings. There was no evidence of epithelial necrosis. Conversion of lamellar bodies to tubular myelin was observed in the air spaces of control animals treated with saline or nonspecific IgG (Fig. 4B). Protocol 2. Forty-three of the 48 animals allocated to this protocol survived the scheduled period of ventilation without complications. Five animals were excluded because of abnormal ECG (arrhythmia or atrioventricular block). Survivors had a body weight of 40 ± 6 g and a final heart rate of 308 ± 21 beats/min. Body weight of the five animals with empty tracheal cannula that were killed immediately after the instillation maneuver was 38 ± 5 g. Final values for lung-thorax compliance and PCO2 in heart blood of animals killed at various times are shown in Table 2. These measurements confirm the rapid effect of the antibody, with a significant drop in compliance after 15 min and no further change at later intervals. Compliance was lower for animals receiving nonspecific rabbit IgG or saline than for nontreated controls at 15-60 min (P < 0.01-0.05; data not shown) but remained, throughout the course of the experiment, significantly higher than for animals receiving antibody (P < 0.01). Vascular-to-alveolar leakage of human albumin and human IgG at various times after administration of the antibody is illustrated in Fig. 5. The kinetics of leakage were the same for both markers, with an equilibrium of ~1.8% in the left lung established within 60 min. Animals in the control groups showed very little leakage, and the differences at 120 min between each of these groups, on one hand, and animals receiving the specific antibody, on the other, were statistically significant for both markers (P < 0.01 for albumin; P < 0.05 for IgG). Light-microscopic examination of lung sections incubated with antibody to human albumin revealed immunoreactive material in the pulmonary vasculature in all animals receiving the marker. There was also immunoreactive material in the air spaces, especially in animals ventilated for 120 min after instillation of monoclonal antibody to SP-B into the airways. Because the permeability markers were measured more precisely in lung lavage fluid by immunodiffusion (see above), we made no efforts to quantify the leak in the histological sections.
, Treatment, antibody to SP-B; marker, human albumin. ,
Treatment, antibody to SP-B; marker, human IgG. , Treatment, rabbit
IgG; marker, human albumin. 
, Treatment, rabbit IgG; marker, human
IgG. 
, Treatment, saline; marker, human albumin. 
, Treatment, saline; marker, human IgG. 
, Treatment, none; marker, human albumin. 
, Treatment, none; marker, human IgG. Values for leakage of albumin and IgG (means ± SD) at 120 min are significantly larger in animals receiving antibody than in each of control groups
(P < 0.01 for albumin;
P < 0.05 for IgG).
Protocol 3. Thirty-seven of the 40 ventilated animals allocated to protocol 3 survived without complications; these animals had a body weight of 43 ± 10 g and a final heart rate of 251 ± 31 beats/min. Two animals were lost because of pneumothorax developing after 60 and 90 min of ventilation; another rabbit was excluded because of mediastinal emphysema diagnosed after 2 h of ventilation. Final values for lung-thorax compliance and PCO2 in heart blood are shown in Table 2. Compliance values for animals receiving antibody or no material were on the same order as in the other experiments (protocols 1 and 2), and most of the animals treated with nonspecific rabbit or mouse IgG showed no adverse reaction. However, two of the animals receiving rabbit IgG showed a prominent fall in compliance to <0.40 ml · cmH2O
1 · kg1
already in the first recording after onset of ventilation. Because of
this variability, the difference in compliance between the antibody-
and IgG-treated groups was not statistically significant.
Cell counts in lung lavage fluid are shown in Table
3. Total cell number was increased
significantly in animals receiving the specific antibody, and in these
animals nearly all the cells recovered from the air spaces were
neutrophilic granulocytes, indicating an acute inflammatory reaction.
In most animals receiving rabbit or mouse IgG, cell counts did not
differ from nontreated controls. However, in the same two IgG-treated
animals that showed a fall in compliance, cell counts were also
increased, with a high proportion of granulocytes, as in animals
receiving the antibody. Linear regression analysis showed, for the
material as a whole, a negative correlation between percent
granulocytes in lavage fluid and compliance
(r = 
0.53,
P < 0.001).
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DISCUSSION
SP-B is a hydrophobic polypeptide with alternating
-helical and 
-sheet domains. The
physiological roles of this protein have not been precisely defined,
but under in vitro conditions, SP-B (alone or in conjunction with other
surfactant proteins) greatly enhances the surface adsorption of
surfactant lipids, and physiologically active surfactant substitutes
can be made from synthetic lipids and SP-B alone or SP-B + SP-C (for
review see Ref. 7). These artificial surfactants (lacking SP-A) exert their function without generating tubular myelin (13). Thus it seems
that SP-B is an indispensable component of the surfactant system,
although its mode of interaction with the surfactant lipids varies
depending on the presence of other components, especially SP-A.
Our present experiments, together with a previous less extensive study
using a cross-reacting antibody (16), document that selective blocking
of SP-B in the neonatal lung leads to severe acute lung disease, with
an immediate fall in compliance to a level comparable to that of
surfactant-deficient immature newborn rabbits (~0.40
ml · cmH2O1 · kg1)
(18), necrosis and desquamation of alveolar epithelium with formation
of hyaline membranes, and leakage of serum proteins into the alveolar
spaces. All these features, similar to those characterizing the
neonatal respiratory distress syndrome (RDS), indicate a loss of
surfactant function, which, at least in part, can be due to direct
inactivation as observed in our pulsating bubble studies (Fig. 2). In
addition, surfactant may become inactivated by plasma proteins leaking
into the air spaces (5, 9, 17). This leak probably occurs from sites of
epithelial injury (15), triggered by shear forces due to defective
surfactant function (12) or by an immunologic cascade with
activation of complement, recruitment of granulocytes to the air
spaces, and release of proteolytic enzymes from the inflammatory cells.
Judged from our present data, the leak does not discriminate between
albumin and IgG, indicating that the "pores" of the damaged
epithelium are significantly larger than the diffusion radius of the
markers.
Congenital absence of SP-B or blocking of SP-B with a specific antibody may prevent the normal conversion of lamellar bodies to tubular myelin, an important step in the life cycle of surfactant. Tubular myelin with normal ultrastructural dimensions can be reconstituted in vitro by mixing appropriate amounts of dipalmitoylphosphatidylcholine, unsaturated phosphatidylglycerol, SP-A, and SP-B in the presence of Ca2+ (19, 21). If an antibody to SP-B is added to the same mixture, the lipids aggregate in a more disorganized fashion without forming tubular myelin (20). Similarly, absence or blocking of SP-B could, under in vivo conditions, cause respiratory failure by interfering with formation of tubular myelin in the alveolar lining layer. This could lead to accumulation of "nonexpanded" lamellar bodies in the alveolar spaces, as suggested by observations in our present study (Fig. 4A), as well as in babies with congenital SP-B deficiency (2, 3) and in mice inoculated with hybridoma cells producing antibodies to SP-B (6).
The exudative lesions developing in the lungs of animals exposed to the monoclonal antibody included recruitment of inflammatory cells, mainly neutrophilic granulocytes, to the alveolar spaces. It seems that, in the present experimental model, neutrophils were attracted to and activated at the site of the immune reaction. If this is so, at least some of the tissue injury may have been caused by free radicals and proteolytic enzymes released by the inflammatory cells. Such a mechanism is probably involved in the pathogenesis of the adult RDS (for review see Ref. 14) and perhaps also in neonatal RDS. However, the rapid fall in lung compliance after instillation of the antibody is probably best explained with a direct inactivation of surfactant. Recruitment of leukocytes to the air spaces is a more prominent feature in the present experimental model than in surfactant-deficient immature newborn animals ventilated for 30-60 min without exposure to the antibody (18). In this context, it is of interest to recall the study by Kawano et al. (8) showing that lung injury induced by surfactant depletion in ventilated adult rabbits is nearly abolished if the animals are first made neutropenic by exposure to nitrogen mustard. All these observations indicate that activated neutrophils may play an essential role in the pathophysiology of acute lung injury, also in the case of primary surfactant deficiency, depletion, or inactivation.
In the experiments conducted according to protocol 3, we noted that some animals reacted to nonspecific rabbit IgG with a substantial recruitment of neutrophils to the air spaces; these animals also showed a fall in compliance on the same order as that seen after tracheal instillation of the specific antibody. Such an inflammatory reaction to IgG was not observed in control animals studied according to protocols 1 and 2 or in our previous study (16). Respiratory failure, similar to that elicited by a monoclonal antibody to SP-B, may occasionally develop as a consequence of other immune reactions triggered by the control antibody preparations (batches of nonspecific rabbit IgG used in protocols 1 and 2 were different from those used in protocol 3). Our in vitro data (Table 1, Fig. 2) indicate no direct effects of IgG on the physical properties of surfactant, not even at concentrations of the antibody exceeding that of the surfactant preparation.
In conclusion, monoclonal antibody to SP-B administered into the airways at birth triggers an acute immune reaction characterized by inactivation of surfactant with an immediate fall in lung compliance, necrosis and desquamation of airway epithelium, development of alveolar hyaline membranes, recruitment of neutrophils, and leakage of serum proteins into the air spaces. The pathology and pathophysiology of this form of experimental neonatal lung injury are reminiscent of neonatal and adult RDS and provide indirect evidence of the fundamental role of SP-B in the pulmonary surfactant system.
ACKNOWLEDGEMENTS
The authors thank Bim Linderholm, Eva Lundberg, and Petru Popa for skillful technical assistance.
FOOTNOTES
Address for reprint requests: G. Grossmann, Div. for Experimental Perinatal Pathology, Karolinska Hospital L1:01, S-171 76 Stockholm, Sweden.
Received 27 March 1996; accepted in final form 14 March 1997.
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ABSTRACT