1 Respiratory Division and 3 Division of Molecular Immunology, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115; and 2 Department of Microbiology, Vanderbilt University, Nashville, Tennessee 37235
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ABSTRACT |
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Although surfactant apoproteins are known to be mediators of innate responses, their relationship to adaptive responses has not been examined extensively. We investigated possible links between surfactant apoproteins and responses to allergens by studying alterations in surfactant apoproteins A, B, and D in a murine model of allergic pulmonary inflammation. Three murine strains (BALB/c, C57BL/6, and 129J) demonstrated increased immunostaining of surfactant apoproteins A and D in nonciliated epithelial cells of noncartilaginous airways after aerosolized challenge. In contrast, surfactant apoprotein B immunostaining was unchanged. Immunoblotting demonstrated increased surfactant A in bronchoalveolar lavage fluid after allergen sensitization and challenge. Surfactant apoprotein A and D induction required T and/or B lymphocyte responses to allergen, since the induction was absent in recombinase-activating gene-deficient mice, which lack functional lymphocytes. We conclude that increased immunoreactivity of two collectins, surfactant apoproteins A and D, occurs within the response to allergen. Our findings support a model in which surfactant apoproteins A and D are important to both innate immunity and adaptive immune responses to allergens.
lung; T lymphocytes; murine models; innate
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INTRODUCTION |
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THE ADAPTIVE AND INNATE IMMUNE responses complement each other in their roles to promote host defenses. Adaptive immunity involves antigen-specific receptors and requires hours to days for differentiation of effector cells. In contrast, innate immunity involves pattern recognition receptors, and the effector stage occurs within minutes to hours of exposure. Although adaptive antigenic responses are known to play essential roles in allergic asthma, the role of innate immunity is less well characterized.
Innate responses involve many cell types and mediators, including surfactant apoproteins (8, 9, 14, 38, 40, 55). The best known function of surfactant and the surfactant apoproteins is to decrease the surface tension in the alveoli. However, surfactant apoproteins also modulate pulmonary inflammatory responses (8, 14, 40, 55).
Two of the surfactant apoproteins, surfactant A (SP-A) and surfactant D (SP-D), are collectins. The collectins are a family of proteins characterized by a collagen-like region and a C-type lectin at their carboxy terminus (20), which also includes mannose-binding protein (18-20, 38). The collectins are important mediators of innate immunity, with their functions including opsonizing bacteria and promoting phagocytosis; mannose-binding protein has also been demonstrated to activate complement (8, 20).
SP-A and SP-D can modulate innate immune responses in the lung. Both SP-A and SP-D can bind and opsonize bacteria (28, 32, 48) and fungi (1, 9, 17, 34, 37, 39, 42, 44, 46, 47, 54). In addition, SP-A can bind viruses such as influenza A and herpes simplex (35, 49, 50) as well as Pneumocystis carinii (57) and is a chemoattractant for macrophages (56). Mice deficient in SP-A are more susceptible to infections resulting from Pseudomonas (30) and Streptococcus (31) compared with wild-type mice. Moreover, SP-A expression is induced during lung inflammation after exposures that include lipopolysaccharide (LPS), bleomycin, and silica (51).
Although allergic pulmonary responses are clearly dependent on adaptive immune responses, the relationship of innate mediators to these responses has not been characterized extensively. Given the potential role of surfactant apoproteins in innate and adaptive in vivo responses, we asked whether the surfactant apoproteins are involved in the pulmonary response to allergen. To investigate pulmonary adaptive responses, we analyzed an in vivo murine model of asthma, elicited by systemic sensitization to the allergen ovalbumin (OVA) followed by aerosolized challenge, resulting in eosinophilic pulmonary infiltrates and airway hyperresponsiveness (AHR; see Refs. 11, 26, 27, 36). We hypothesized that immune responses observed in this allergic model involve innate immunity, specifically the collectin surfactant apoproteins SP-A and SP-D. To test our hypothesis, we compared the expression of collectins SP-A and SP-D with that of a noncollectin hydrophobic surfactant apoprotein (SP-B) after allergic sensitization and challenge. In our murine model, increased AHR was associated with changes in SP-A and SP-D expression. Expression of SP-A and SP-D within the nonciliated epithelial cells of the noncartilaginous airways (bronchiolar cells) increases after allergen sensitization and challenge, suggesting that the bronchiolar cells may participate in the pulmonary immune response to allergens. These results are also consistent with a role for SP-A and SP-D in pulmonary adaptive allergic responses.
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METHODS |
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Mice.
Eight-week-old male BALB/c, C57BL/6, 129J, and recombinase-activating
gene-1 (RAG1)-deficient mice on a C57BL/6 background were purchased
from Jackson Laboratories (Bar Harbor, ME) and stored in a sterile
environment. Mice that overexpress a mutated form of the inhibitor of
B
[I
B
(
N), C57BL/6 background] and mice deficient in
c-Rel (C57BL/6 background; generous gift of H. C. Liou), a
constituent of nuclear factor (NF)-
B, were generated as previously
described (2, 11, 33). Mice were fed rodent diet 5001 (Harlan, Madison, WI). The mice were maintained according to the
guidelines of the Committee on Animals of the Harvard Medical School
and the Committee on the Care and Use of Laboratory Animals of the
Institute of Laboratory Animal Resources, National Research Council.
Protocol for allergen sensitization and challenge. Mice were sensitized and challenged with OVA as previously described (26). Briefly, mice were sensitized by intraperitoneal injection of 10 µg chicken OVA and 1 mg Al(OH)3 (Alum) on days 0 and 7. On days 14-20, mice received daily aerosolized OVA challenges with 6% OVA for 25 min/day. OVA was dissolved in 0.5× PBS. Control mice received 1 mg Alum in PBS ip on days 0 and 7 and were nebulized with PBS on days 14-20. An ultrasonic nebulizer (model 5000; DeVilbiss, Somerset, PA) was used for nebulizations in a chamber.
Determination of AHR. After the last aerosol challenge (24 h), AHR was assessed using whole body plethysmography (Buxco, Troy, NY), as has been described previously (16). For the kinetic studies, AHR was assessed at time 0 (naive mice), day 15 (after the first aerosolized challenge), day 17 (after the third challenge), day 19 (after the fifth challenge), and day 21 (after the seventh challenge). Mice were placed in individual chambers. Methacholine was nebulized in the chambers via an inlet at a concentration of 100 mg/ml for 3 min, since this dose of methacholine produces significantly increased airway resistance compared with baseline measurements in mice sensitized and challenged with OVA, but not in PBS-exposed mice (13). Readings were averaged over 10 min from the beginning of the nebulization. The whole body plethysmography system measures changes in box pressure during expiration and inspiration, allowing the calculation of enhanced pause (Penh), which directly correlates with airway resistance (13, 16). Baseline airway resistance was determined by measuring Penh after aerosolized PBS.
Western (immunoblotting) analysis. For Western analysis, 1 ml of bronchoalveolar lavage (BAL) fluid was centrifuged at 7,000 g for 10 min to remove cells and then at 11,000 g for 40 min. The supernatant was removed, and the pellet (containing SP-A) was resuspended in 100 µl of running buffer. Samples were loaded on the gel, subjected to electrophoresis, and electroblotted on nytran. The blot was blocked in 5% milk in PBS with 0.1% Tween 20 (PBST; Fisher Scientific) for 1 h at room temperature. Rabbit anti-SP-A antisera (generous gift of E. Ingenito and R. Mora) was diluted 1:500 in PBST and applied to the blot for 1 h at room temperature. The blot was washed in PBST, and peroxidase-labeled goat anti-rabbit secondary antibody (Pierce Chemical, Rockford, IL) diluted 1:5,000 in 5% milk in PBST was applied for 30 min at room temperature. The blot was washed in 5% milk in PBST, then in PBST, and finally in PBS. The location of SP-A (monomer molecular mass 29 kDa) was identified by Renaissance Western Chemiluminescence (NEN Life Sciences, Boston, MA), following kit instructions. The densities of the individual bands were compared using densitometry ImageQuant software (Molecular Dynamics, Sunnyvale, CA).
Immunohistochemical analysis. For immunohistochemical analysis, the lung tissue samples were removed from the thoracic cavity and snap-frozen in liquid nitrogen. Lung tissue samples were obtained from each time point. Frozen sections 5 µm thick were cut, and the tissues were screened using hematoxylin and eosin to determine that alveolar tissue and at least three nonciliated bronchioles were visible in the section. Tissue sections meeting these standards were stained using a modified avidin-biotin technique (15). The time points analyzed were controls (naive and OVA-sensitized, aerosolized PBS challenge), day 2 (after first OVA ip injection), day 8 (after second OVA ip injection), day 13 (day before aerosol challenge), day 15 (after the first aerosolized OVA challenge), day 17 (after the third aerosolized OVA challenge), day 19 (after the fifth aerosolized OVA challenge), and day 21 (after the seventh aerosolized OVA challenge). For each time point, n = 3-5 determinations. The primary antibodies included an IgG fraction of rabbit polyclonal antiserum against bovine SP-A used at 1:1,000, a whole rabbit polyclonal antiserum against bovine SP-B used at 1:1,000 (generous gifts of R. Mora and E. P. Ingenito), and a whole rabbit polyclonal antiserum against rat SP-D (generous gift of E. Crouch) used at 1:750. The cross-reactivity of these antisera to murine apoproteins and the specificity of these antisera for their respective apoproteins have been shown previously (22, 41). In addition, the immunostaining patterns were replicated using a second set of whole rabbit antisera against murine SP-D, human SP-A, and bovine SP-B (Chemicon International, Temecula, CA). The SP-B immunostaining was enhanced by tyramide amplification using the TSA Biotin System kit, following the manufacturer's instructions (NEN). Negative controls consisted of substituting PBS and purified rabbit IgG for the primary antibody. An experienced reader (Haley) scored the slides in a blinded fashion. All of the nonciliated bronchioles and alveolar tissue from at least one lobe were examined and scored for each animal. The intensity of immunostaining was assessed by a semiquantitative method as follows: 0 designating no immunostaining, 1+ designating faint intensity of immunostaining, 2+ designating moderate immunostaining, and 3+ designating intense immunostaining.
Statistical analysis. Data analysis was performed using Sigma Stat for airway measurements. Parametric data were analyzed with the Tukey-Kramer test, and nonparametric data were analyzed by the Wilcoxon-Kruskal-Wallace rank-sum test. Data are reported as means ± SE. Statistical significance was defined as P < 0.05.
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RESULTS |
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Surfactant apoprotein expression after OVA sensitization and
challenge.
Three murine strains (BALB/c, C57BL/6, and 129J) sensitized and
challenged with the antigen OVA developed peribronchial and perivascular eosinophilic and lymphocytic infiltrates, similar to
previous studies by our laboratory analyzing the BALB/c strain (26). Histological examination of all three murine strains
on day 21 (after the seventh aerosolized OVA challenge)
confirmed the development of abundant inflammatory infiltrates (Fig.
1), concomitant with AHR, increased serum
IgE, and eosinophilia, similar to our previous analyses of this model
(11, 13, 26, 27, 36)
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Dependence on intact lymphocytic functioning.
To determine whether the increased expression of SP-A and SP-D was a
nonspecific reaction to the presence of pulmonary inflammation or a
specific response requiring intact B and/or T lymphocyte functioning,
we examined mice with defects in their responses to OVA sensitization
and aerosolized challenge. We first examined the responses of mice
deficient in c-Rel, a lymphoid predominant NF-B component, after OVA
sensitization and aerosolized challenge. Prior reports indicated that
these mice do not develop significant pulmonary infiltrates after OVA
sensitization and aerosolized challenge (11). Compared
with wild-type C57BL/6 controls, the c-Rel-deficient mice demonstrated
attenuated IgE levels after OVA sensitization and aerosolized challenge
(11). However, T cells from mice deficient in c-Rel
express normal amounts of the costimulatory molecules CD28 and CD40
ligand after stimulation with anti-CD3 (33). These
findings indicate that mice deficient in c-Rel have diminished, but not
absent, T cell responses. We used immunostaining to evaluate the
expression of SPA in c-Rel-deficient mice after OVA sensitization and
aerosolized challenge. Naive c-Rel-deficient mice demonstrate
constitutive SP-A expression similar to that of their background
strain, C57BL/6 (Fig. 6A). After OVA sensitization and aerosolized challenge, c-Rel-deficient mice demonstrate increased bronchiolar immunostaining for
SP-A, without changes in alveolar epithelial cell staining (Fig.
6B). As was observed in the wild-type C57BL/6 mice, this
increased expression of SP-A persisted for at least 48 h (Fig.
6C). Thus the increased expression of SP-A after OVA
sensitization and aerosolized challenge does not require allergic
pulmonary inflammation but may depend on aspects of lymphocyte
activation that remain active in c-Rel-deficient mice.
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DISCUSSION |
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This study demonstrates that expression of collectins SP-A and SP-D is altered in the airways after allergen sensitization and challenge in a murine model of asthma. Three murine strains, BALB/c, C57BL/6, and 129J, were analyzed. All three strains demonstrated increased expression of SP-A and SP-D in the bronchiolar cells. Analysis of BAL fluid by immunoblotting demonstrated increased SP-A protein after OVA sensitization and challenge, suggesting that the increased immunostaining was the result of increased protein expression. In contrast, there were no changes in the bronchiolar cell expression of SP-B, a noncollectin surfactant apoprotein that is critical in reducing surface tension in the lung. Thus far, there have not been reports of SP-B modulating the function of leukocytes (40).
The increased surfactant apoprotein expression was also observed
in c-Rel-deficient and IB
(
N) transgenic mice, both of which
demonstrate attenuated responses to OVA sensitization and challenge.
This finding suggests that the increased surfactant apoprotein
expression does not require the development of parenchymal pulmonary
infiltrates. Furthermore, our data also show that the increased
expression of SP-A and SP-D is not seen in mice deficient in RAG1,
which lack any functioning T and/or B cells. Together, these data
suggest that some degree of lymphocyte activity is required for the
increased SP-A and SP-D expression after OVA sensitization and
aerosolized challenge. Indeed, the presence of increased surfactant
apoprotein expression in the context of diminished B and/or T cell
function, and the absence in the context of ablated B and/or T cell
function, suggests that collectins, important mediators of innate
responses, are also relevant to pulmonary adaptive allergic responses.
The increase in SP-A and SP-D was observed in the bronchiolar cells,
which are critical effector cells in pulmonary injury and repair. In
mice, the majority of the bronchiolar cells express Clara cell-specific
protein/CC10, the major secretory product of Clara cells
(12). Arsalane and colleagues (3) showed
decreased expression of Clara cell-specific protein after intratracheal LPS. In addition to models of acute lung injury, alterations in bronchiolar cell function have also been demonstrated in asthma, with
decreased Clara cell-specific protein demonstrated in asthmatic vs.
control subjects (45). Bronchiolar cells may have
anti-inflammatory properties, since Clara cell-specific protein
decreases expression of interferon- in cultured peripheral blood
mononuclear cells (10) and inhibits cytosolic
phospholipase A2-mediated fibroblast chemotaxis
(29). Our data suggest that bronchiolar cells may have a
role in adaptive allergic responses.
Investigations in nonallergic models have demonstrated that SP-A and
SP-D modulate adaptive pulmonary immune responses. SP-A and SP-D
decrease some in vitro responses (4, 5, 7, 53) but augment
others (23-25). SP-A and SP-D also decrease
proliferation of human peripheral blood lymphocytes stimulated with
anti-CD3 or phytohemagglutinin (4, 5). Additionally, SP-A
decreases cytokine expression in human pulmonary macrophages stimulated with Candida albicans (43) and in human
eosinophils stimulated with ionomycin (7). In contrast,
SP-A increases proliferation and the release of both IgA and IgG from
cultured rat splenocytes stimulated with concanavalin A
(24) and augments the expression of tumor necrosis
factor-, IL-1
, and IL-6 by both the monocyte-like cell line THP-1
(25) and unstimulated human peripheral blood mononuclear
cells (23). Our findings differ from previous
investigations of the roles of surfactant apoproteins in immunological
responses in that the current study focuses on an allergic adaptive
immune response.
Previous in vitro analyses also suggest a role for SP-A and SP-D in asthma. The carbohydrate recognition domain of both SP-A and SP-D can bind the most common allergen associated with the dust mite, Der p 1 (52). Both SP-A and SP-D decreased lymphocyte proliferation after exposure to Der p 1 from asthmatic children (53). The effects of SP-A and SP-D were dose dependent and were also observed with pretreating the cultures with the surfactant apoproteins. Both SP-A and SP-D decrease lymphocyte proliferation and cytokine production in asthmatic patients (53). These studies, together with our in vivo analyses indicating an upregulation of SP-A and SP-D in bronchiolar cells concomitant with increased AHR, support the notion that SP-A and SP-D may play a role in allergic asthma.
Our proposal that the increased expression of SP-A and SP-D after OVA sensitization and aerosolized challenge involves a T cell-dependent mechanism is supported by recent studies. Ikegami and colleagues (21) demonstrated that mice that overexpress IL-4 in Clara cells have increased expression of both SP-A and SP-D. Moreover, the expression of SP-D was significantly greater than that predicted by the increase in lung-saturated phosphatidylcholine, consistent with regulation of SP-D by IL-4 (21).
Increased surfactant apoprotein expression could modulate the pulmonary response to allergens in several possible ways. One possible explanation for the increased SP-A and SP-D expression is a compensatory increase in surfactant production to offset the dysfunction caused by the influx of serum proteins that occurs in the alveolar space after an allergic challenge. However, although this mechanism is possible, it is not the most likely explanation of our results, since the expression of the hydrophobic surfactant apoprotein B did not change after OVA sensitization and aerosolized challenge. Moreover, the location of the increased SP-A and SP-D expression in our immunohistochemical studies was the bronchiolar epithelial cells. In our experiments, the alveolar epithelial cells, which would be expected to have greater impact on the alveolar space than the bronchiolar cells, did not change their expression of surfactant apoproteins after OVA sensitization and challenge.
Increased expression of SP-A and SP-D may be an integral part of the pulmonary adaptive allergic response. Thus our findings imply a novel function for the surfactant apoproteins. We speculate that the increased expression of SP-A and SP-D in our model depends on lymphocyte-associated cytokines.
Support for the proposal that alterations in the expression of SP-A and SP-D are an integral part of the pulmonary response to allergens, as opposed to a nonspecific response to pulmonary inflammation, is found in our in vivo demonstration that SP-A and SP-D, but not SP-B, are upregulated after allergen sensitization concomitant with the kinetics of allergen-induced AHR. Additional support for a role for SP-A and SP-D in adaptive allergic responses is found in our analysis of models in which the adaptive responses are disrupted. In RAG1-deficient mice, the inability to mount an adaptive allergic response after OVA sensitization is paralleled by a loss of the increased SP-A and SP-D expression in bronchiolar cells. However, increased SP-A and SP-D expression is preserved in the c-Rel mice despite diminished pulmonary infiltrates after OVA sensitization and challenge. Together, these data suggest that it is unlikely that the alterations in SP-A and SP-D expression are nonspecific responses to the presence of pulmonary inflammation but rather are responses to B and/or T cell activation. Interestingly, after LPS administration, both SP-A and SP-B expression decrease, which is a different pattern of surfactant apoprotein expression than that observed in the current study (22).
In summary, our data demonstrate that SP-A and SP-D, but not SP-B, are altered after OVA sensitization and challenge in a murine model. The changes in the expression of these apoproteins were conserved among three murine strains, BALB/c, C57BL/6, and 129J, and thus were not strain-specific responses. The innate immunity mediators SP-A and SP-D may play a role in the pulmonary inflammatory responses to allergen, since allergen-induced expression of SP-A and SP-D in bronchiolar cells is dependent on functioning T and/or B cells. SP-A and SP-D may be important links between the innate and adaptive immune systems in the pulmonary response to allergen.
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ACKNOWLEDGEMENTS |
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W thank Drs. Mary E. Sunday, Joan Stein-Streilein, Carolyn Fleming, Robert Westlake, Thomas Mueller, Christian Schroeter, and Kevan Hartshorn for thoughtful comments during the preparation of this manuscript and Dr. Richard Riese for assistance with the immunoblotting technique.
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FOOTNOTES |
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This work was supported by National Heart, Lung, and Blood Institute Grant HL-56723 (P. W. Finn).
Address for reprint requests and other correspondence: P. W. Finn, Pulmonary and Critical Care Division, Brigham and Women's Hospital, 75 Francis St., Boston, MA 02115 (E-mail: pwfinn{at}rics.bwh.harvard.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/ajplung.00117.2001
Received 28 March 2001; accepted in final form 26 October 2001.
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REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Allen, MJ,
Harbeck R,
Smith B,
Voelker DR,
and
Mason RJ.
Binding of rat and human surfactant proteins A and D to Aspergillus fumigatus conidia.
Infect Immun
67:
4563-4569,
1999
2.
Aronica, MA,
Mora AL,
Mitchell DB,
Finn PW,
Johnson JE,
Sheller JR,
and
Boothby MR.
Preferential role for NF-kappa B/Rel signaling in the type 1 but not type 2 T cell-dependent immune response in vivo.
J Immunol
163:
5116-5124,
1999
3.
Arsalane, K,
Broeckaert F,
Knoops B,
Wiedig M,
Toubeau G,
and
Bernard A.
Clara cell specific protein (CC16) expression after acute lung inflammation induced by intratracheal lipopolysaccharide administration.
Am J Respir Crit Care Med
161:
1624-1630,
2000
4.
Borron, P,
Veldhuizen RAW,
Lewis JF,
Possmayer F,
Caveney A,
Inchley K,
McFadden RG,
and
Fraher LJ.
Surfactant associated protein-A inhibits human lymphocyte proliferation and IL-2 production.
Am J Cell Mol Biol
15:
115-121,
1996[Abstract].
5.
Borron, PJ,
Crouch EC,
Lewis JF,
Wright JR,
Possmayer F,
and
Fraher LJ.
Recombinant rat surfactant-associated protein D inhibits human T lymphocyte proliferation and IL-2 production.
J Immunol
161:
4599-4603,
1998
6.
Cernadas, M,
De Sanctis GT,
Krinzman SJ,
Mark DA,
Donovan CE,
Listman JA,
Kobzik L,
Kikutani H,
Christiani DC,
Perkins DL,
and
Finn PW.
CD23 and allergic pulmonary inflammation: potential role as an inhibitor.
Am J Respir Cell Mol Biol
20:
1-8,
1999
7.
Cheng, G,
Ueda T,
Nakajima H,
Nakajima A,
Kinjyo S,
Motojima S,
and
Fukuda T.
Suppressive effects of SP-A on ionomycin-induced IL-8 production and release by eosinophils.
Int Arch Allergy Immunol
117:
59-62,
1998[ISI][Medline].
8.
Crouch, EC.
Collectins and pulmonary host defense.
Am J Respir Cell Mol Biol
19:
177-201,
1998
9.
Crouch, EC.
Surfactant protein-D and pulmonary host defense.
Respir Res
1:
93-108,
2000[Medline].
10.
Dierynck, I,
Bernard A,
Roels H,
and
De Ley M.
Potent inhibition of both human interferon- production and biologic activity by the Clara cell protein CC16.
Am J Respir Cell Mol Biol
12:
205-210,
1995[Abstract].
11.
Donovan, CE,
Mark DA,
He HZ,
Liou HC,
Kobzik L,
Wang Y,
De Sanctis GT,
Perkins DL,
and
Finn PW.
NF-kappa B/Rel transcription factors: c-Rel promotes airway hyperresponsiveness and allergic pulmonary inflammation.
J Immunol
163:
6827-6833,
1999
12.
Fanucchi, MV,
Murphy ME,
Buckpitt AR,
Philpot RM,
and
Plopper CG.
Pulmonary cytochrome P450 monooxygenase and Clara cell differentiation in mice.
Am J Respir Cell Mol Biol
17:
302-314,
1997
13.
Fleming, CM,
He H,
Ciota A,
Perkins D,
and
Finn PW.
Administration of pentoxifylline during allergen sensitization dissociates pulmonary allergic inflammation from airway hyperresponsivesness.
J Immunol
167:
1703-1711,
2001
14.
Griese, M.
Pulmonary surfactant in health and human lung diseases: state of the art.
Eur Respir J
13:
1455-1476,
1999
15.
Haley, KJ,
Patidar K,
Zhang F,
Emanuel RL,
and
Sunday ME.
Tumor necrosis factor induces a partial neuroendocrine cell phenotype in undifferentiated small cell lung carcinoma cell lines.
Am J Physiol Lung Cell Mol Physiol
275:
L311-L321,
1998
16.
Hamelmann, E,
Schwarze J,
Takeda K,
Oshiba A,
Larsen GL,
Irvin CG,
and
Gelfand EW.
Noninvasive measurement of airway responsiveness in allergic mice using barometric plethysmography.
Am J Respir Crit Care Med
156:
766-775,
1997
17.
Hartshorn, KL,
Crouch E,
White MR,
Colamussi ML,
Kakkanatt A,
Tauber B,
Shepherd V,
and
Sastry KN.
Pulmonary surfactant proteins A and D enhance neutrophil uptake of bacteria.
Am J Physiol Lung Cell Mol Physiol
274:
L958-L969,
1998
18.
Holmskov, U,
Malhotra R,
Sim RB,
and
Jensenius JC.
Collectins: collagenous C-type lectins of the innate immune defense system.
Immunol Today
15:
67-74,
1994[ISI][Medline].
19.
Holmskov, UL.
Collectins and collectin receptors in innate immunity.
APMIS Suppl
100:
1-59,
2000.
20.
Hoppe, HJ,
and
Reid KBM
Collectins, soluble proteins containing collagenous regions and lectin domains, and their roles in innate immunity.
Protein Sci
3:
1143-1158,
1994
21.
Ikegami, M,
Whitsett JA,
Chroneos ZC,
Ross GF,
Reed JA,
Bachurski CJ,
and
Jobe AH.
IL-4 increases surfactant and regulates metabolism in vivo.
Am J Physiol Lung Cell Mol Physiol
278:
L75-L80,
2000
22.
Ingenito, EP,
Mora R,
Cullivan M,
Marzan Y,
Haley K,
Mark L,
and
Sonna LA.
Decreased SP-B expression and surfactant dysfunction in a murine model of acute lung injury.
Am J Respir Cell Mol Biol
25:
35-44,
2001
23.
Kremlev, SG,
and
Phelps DS.
Surfactant protein A stimulation of inflammatory cytokine and immunoglobulin production.
Am J Physiol Lung Cell Mol Physiol
267:
L712-L719,
1994
24.
Kremlev, SG,
Umstead TM,
and
Phelps DS.
Effects of surfactant protein A and surfactant lipids on lymphocyte proliferation in vitro.
Am J Physiol Lung Cell Mol Physiol
267:
L357-L364,
1994
25.
Kremlev, SG,
Umstead TM,
and
Phelps DS.
Surfactant protein A regulates cytokine production in the monocytic cell line THP-1.
Am J Physiol Lung Cell Mol Physiol
272:
L996-L1004,
1997
26.
Krinzman, SJ,
De Sanctis GT,
Cernadas M,
Kobzik L,
Listman JA,
Christiani DC,
Perkins DL,
and
Finn PW.
T cell activation in a murine model of asthma.
Am J Physiol Lung Cell Mol Physiol
271:
L476-L483,
1996
27.
Krinzman, SJ,
De Sanctis GT,
Cernadas M,
Mark D,
Wang Y,
Listman J,
Kobzik L,
Donovan C,
Nassr K,
Katona I,
Christiani DC,
Perkins DL,
and
Finn PW.
Inhibition of T cell costimulation abrogates airway hyperresponsiveness in a murine model.
J Clin Invest
98:
2693-2699,
1996
28.
Kuan, SF,
Rust K,
and
Crouch E.
Interactions of surfactant protein D with bacterial lipopolysaccharides. Surfactant protein D is an Escherichia coli-binding protein in bronchoalveolar lavage.
J Clin Invest
90:
97-106,
1992[ISI][Medline].
29.
Lesur, O,
Bernard A,
Arsalane K,
Lauwerys R,
RBégin Cantin A,
and
Lane D.
Clara cell protein (CC-16) induces a phospholipase A2-mediated inhibition of fibroblast migration in vitro.
Am J Respir Crit Care Med
152:
290-297,
1995[Abstract].
30.
Levine, AM,
Kurak KE,
Bruno MD,
Stark JM,
Whitsett JA,
and
Korfhagen TR.
Surfactant protein-A-deficient mice are susceptible to Pseudomonas aeruginosa infection.
Am J Respir Cell Mol Biol
19:
700-708,
1998
31.
Levine, AM,
Kurak KE,
Wright JR,
Watford WT,
Bruno MD,
Ross GF,
Whitsett JA,
and
Korfhagen TR.
Surfactant protein-A binds group B streptococcus enhancing phagocytosis and clearance from lungs of surfactant protein-A-deficient mice.
Am J Respir Cell Mol Biol
20:
279-286,
1999
32.
Lim, BL,
Wang JY,
Holmskov U,
Hoppe HJ,
and
Reid KBM
Expression of the carbohydrate recognition domain of lung surfactant protein D and demonstration of its binding to lipopolysaccharides of gram-negative bacteria.
Biochem Biophys Res Commun
202:
1674-1680,
1994[ISI][Medline].
33.
Liou, HC,
Jin Z,
Tumang J,
Andjelic S,
Smith KA,
and
Liou ML.
c-Rel is crucial for lymphocyte proliferation but dispensable for T cell effector function.
Int Immunol
11:
361-371,
1999
34.
Madan, T,
Eggleton P,
Kishore U,
Strong P,
Aggrawal SS,
Sarma PU,
and
Reid KB.
Binding of pulmonary surfactant proteins A and D to Aspergillus fumigatus conidia enhances phagocytosis and killing by human neutrophils and alveolar macrophages.
Infect Immun
65:
3171-3179,
1997[Abstract].
35.
Malhotra, R,
Haurum JS,
Thiel S,
and
Sim RB.
Binding of human collectins (SP-A and MBP) to influenza virus.
Biochem J
304:
455-461,
1994[ISI][Medline].
36.
Mark, DA,
Donovan CE,
De Sanctis GT,
He HZ,
Cernadas M,
Kobzik L,
Perkins DL,
Sharpe A,
and
Finn PW.
B7-1 (CD80) and B7-2 (CD86) have complementary roles in mediating allergic pulmonary inflammation and airway hyperresponsiveness.
Am J Respir Cell Mol Biol
22:
265-271,
2000
37.
McNeely, TB,
and
Coonrod JD.
Aggregation and opsonization of type A but not type B Hemophilus influenzae by surfactant protein A.
Am J Respir Cell Mol Biol
11:
114-122,
1994[Abstract].
38.
Medzhitov, R,
and
Janeway CJ.
Innate immunity.
N Engl J Med
343:
338-344,
2000
39.
Pikaar, JC,
Voorhout WF,
van Golde LM,
Verhoef J,
van Strijp JA,
and
van Iwaarden JF.
Opsonic activities of surfactant proteins A and D in phagocytosis of gram-negative bacteria by alveolar macrophages.
J Infect Dis
172:
481-489,
1995[ISI][Medline].
40.
Pison, U,
Neuendank MA,
Weibach S,
and
Pietschmann S.
Host defense capacities of pulmonary surfactant: evidence for "non-surfactant" functions of the surfactant system.
Eur J Clin Invest
24:
586-599,
1994[ISI][Medline].
41.
Reading, PC,
Morey LS,
Crouch EC,
and
Anders EM.
Collectin-mediated antiviral host defense of the lung: evidence from influenza virus infection of mice.
J Virol
71:
8204-8212,
1997[Abstract].
42.
Restrepo, CI,
Dong Q,
Savov J,
Mariencheck WI,
and
Wright JR.
Surfactant protein D stimulates phagocytosis of Pseudomonas aeruginosa by alveolar macrophages.
Am J Respir Cell Mol Biol
21:
576-585,
1999
43.
Rosseau, S,
Hammeri P,
Maus U,
Gunther A,
Seeger W,
Grimminger F,
and
Lohmeyer J.
Surfactant protein A down-regulates proinflammatory cytokine production evoked by Candida albicans in human alveolar macrophages and monocytes.
J Immunol
163:
4495-4502,
1999
44.
Schelenz, S,
Malhotra R,
Sim RB,
Holmskov U,
and
Bancroft GJ.
Binding of host collectins to the pathogenic yeast Cryptococcus neoformans: human surfactant protein D acts as an agglutinin for acapsular yeast cells.
Infect Immun
63:
3360-3366,
1995[Abstract].
45.
Shijubo, N,
Itoh Y,
Yamaguchi T,
Imada A,
Hirasawa M,
Yamada T,
Kawai T,
and
Abe S.
Clara cell protein-positive epithelial cells are reduced in small airways of asthmatics.
Am J Respir Crit Care Med
160:
930-933,
1999
46.
Tenner, AJ,
Robinson SL,
Borchelt J,
and
Wright JR.
Human pulmonary surfactant protein (SP-A), a protein structurally homologous to C1q, can enhance FcR- and CR1-mediated phagocytosis.
J Biol Chem
264:
13923-13928,
1989
47.
van Iwaarden, F,
Welmers B,
Verhoef J,
Haagsman HP,
and
van Golde LMG
Pulmonary surfactant protein A enhances the host-defense mechanism of rat alveolar macrophages.
Am J Respir Cell Mol Biol
2:
91-98,
1990[ISI][Medline].
48.
van Iwaarden, JF,
Pikaar JC,
Storm J,
Brouwer E,
Verhoef J,
Oosting RS,
van Golde LMG,
and
van Strijp JGA
Binding of surfactant protein A to the lipid A moiety of bacterial lipopolysaccharides.
Biochem J
303:
407-411,
1994[ISI][Medline].
49.
van Iwaarden, JF,
van Strijp JAG,
Ebskamp MJM,
Welmers AC,
Verhoef J,
and
van Golde LMG
Surfactant protein A is opsonin in phagocytosis of herpes simplex virus type 1 by rat alveolar macrophages.
Am J Physiol Lung Cell Mol Physiol
261:
L204-L209,
1991
50.
van Iwaarden, JF,
van Strijp JAG,
Visser H,
Haagsman HP,
Verhoef J,
and
van Golde LMG
Binding of surfactant protein A (SP-A) to Herpes simplex virus type 1-infected cells is mediated by the carbohydrate moiety of SP-A.
J Biol Chem
267:
25039-25043,
1992
51.
Viviano, CJ,
Bakewell WE,
Dixon D,
Dethloff LA,
and
Hook GER
Altered regulation of surfactant phospholipid and protein A during acute pulmonary inflammation.
Biochim Biophys Acta
1259:
235-244,
1995[ISI][Medline].
52.
Wang, JY,
Kishore U,
Lim BL,
Strong P,
and
Reid KBM
Interaction of human lung surfactant proteins A and D with mite (Dermatophagoides pteronyssinus) allergens.
Clin Exp Immunol
106:
367-373,
1996[ISI][Medline].
53.
Wang, JY,
Shieh CC,
You PF,
Lei HY,
and
Reid KBM
Inhibitory effect of pulmonary surfactant proteins A and D allergen induced lymphocyte proliferation and histamine release in children with asthma.
Am J Respir Crit Care Med
158:
510-518,
1998
54.
White, MR,
Crouch E,
Chang D,
Sastry K,
Guo N,
Engelich G,
Takahashi K,
Ezekowitz RA,
and
Hartshorn KL.
Enhanced antiviral and opsonic activity of a human mannose-binding lectin and surfactant protein D chimera.
J Immunol
165:
2108-2115,
2000
55.
Wright, JR.
Immunomodulatory functions of surfactant.
Physiol Rev
77:
931-962,
1997
56.
Wright, JR,
and
Youmans DC.
Pulmonary surfactant protein A stimulates chemotaxis of alveolar macrophage.
Am J Physiol Lung Cell Mol Physiol
264:
L338-L344,
1993
57.
Zimmerman, PE,
Voelker DR,
McCormack FX,
Paulsrud JR,
and
Martin WJI
120-kD surface glycoprotein of Pneumocystis carinii is a ligand for surfactant protein A.
J Clin Invest
89:
143-149,
1992[ISI][Medline].