Complement-dependent immune complex-induced bronchial
inflammation and hyperreactivity
Nicholas W.
Lukacs1,
M.
Michael
Glovsky2, and
Peter A.
Ward2
1 Department of Pathology, University of Michigan
Medical School, Ann Arbor, Michigan 48109-0602; and 2 Asthma and
Allergy Center, Huntington Hospital, Pasadena, California 91109-7013
 |
ABSTRACT |
Bronchoconstriction
responses in the airway are caused by multiple insults and are the
hallmark symptom in asthma. In an acute lung injury model in mice, IgG
immune complex deposition elicited severe airway hyperreactivity that
peaked by 1 h, was maintained at 4 h, and was resolved by
24 h. The depletion of complement with cobra venom factor (CVF)
markedly reduced the hyperreactive airway responses, suggesting that
complement played an important role in the response. Blockade of C5a
with specific antisera also significantly reduced airway
hyperreactivity in this acute lung model. Complement depletion by CVF
treatment significantly reduced tumor necrosis factor and histamine
levels in bronchoalveolar lavage fluids, correlating with reductions in
airway hyperreactivity. To further examine the role of specific
complement requirement, we initiated the immune complex response in
C5-sufficient and C5-deficient congenic animals. The airway
hyperreactivity response was partially reduced in the C5-deficient
mice. Complement depletion with CVF attenuated airway hyperreactivity
in the C5-sufficient mice but had a lesser effect on the airway
hyperreactive response and histamine release in bronchoalveolar lavage
fluids in C5-deficient mice. These data indicate that acute
lung injury in mice after deposition of IgG immune complexes induced
airway hyperreactivity that is C5 and C5a dependent.
histamine; tumor necrosis factor; lung
 |
INTRODUCTION |
MULTIPLE PATHWAYS AND
MECHANISMS can mediate the induction of airway hyperreactivity
(7, 8, 18, 47, 52). Classic investigations have described
IgE-mediated mast cell activation followed by an intense late-phase
inflammatory response that includes the presence of lymphocytes,
monocytes, and eosinophils. Although the mediators for acute and
chronic airway responses have not been completely identified, it has
been established that the severity of the airway response is a function
of the intensity of the inflammation (7, 8, 18, 47, 52).
Several specific and nonspecific events are likely involved and
contribute to the induction of airway hyperreactivity.
Acute lung injury that is induced by IgG immune complex deposition in
the lung includes a vascular leak syndrome, significant recruitment and
activation of leukocytes, and damage of vascular endothelial cells and
alveolar epithelial cells (27, 49, 62). These types of
events are observed in many diseases including autoimmune diseases and
specific types of immune-mediated diseases such as allergic
aspergillosis. In these diseases, deposition of immune complexes is
often associated with a severe hemorrhagic alveolitis in association
with intense infiltration of neutrophils into the interstitial and
intra-alveolar compartments within 1-4 h (26, 37, 50,
67). Subsequently, the inflammatory response results in the loss
of integrity of the alveolar capillary wall. Neutrophils recruited to
the site are activated and release a number of mediators, further
damaging the inflamed tissue. The response is dependent on the
activation of a number of complement proteins (45, 46).
Inhibition of complement components or complement activation products
attenuates tissue damage. Although the response in animal models of IgG
immune complex-induced inflammation in the lung has been extensively
studied, the ability of immune complex-induced responses to alter lung
function has not been well analyzed. In the present study, we
demonstrate that IgG immune complex-induced pulmonary inflammation
induces airway hyperreactivity in murine lungs in a manner that is
complement dependent.
 |
MATERIALS AND METHODS |
Animals.
Female CBA/J mice were purchased from Jackson Laboratory (Bar Harbor,
ME) and maintained under standard pathogen-free conditions. C5-deficient mice (B10.D2 "old line") and C5-sufficient mice
(B10.D2 "new line") were also obtained from the Jackson Laboratory
and are congenic mouse strains.
Induction of pulmonary immune complex inflammation.
Polyclonal rabbit anti-BSA IgG antibody (50 µg/mouse in 50 µl) was
injected intratracheally into CBA/J mice followed by an injection of
BSA (1 mg) via the tail vein. The mice were euthanized at various time
points post-BSA injection (1, 4, and 24 h). The parameters
examined included bronchoalveolar lavage (BAL) fluid content such as
leukocytes, tumor necrosis factor (TNF), and histamine and quantitation
of airway physiological changes.
To deplete animals of complement, cobra venom factor (CVF; 200 U/kg)
was injected intraperitoneally the night before surgery. This dose has
previously been shown to reduce C3 levels in plasma to <3% of normal
levels (17, 34).
Measurement of airway hyperreactivity.
Airway hyperreactivity was measured with a mouse plethysmograph
specifically designed for the low tidal volumes (Buxco, Troy, NY) as
previously described (8-11). Briefly, the mouse to be
tested was anesthetized with pentobarbital sodium and intubated via
cannulation of the trachea with an 18-gauge metal tube. The mouse
was subsequently ventilated with a Harvard pump ventilator (tidal
volume = 0.4 ml, frequency = 120 breaths/min, positive
end-expiratory pressure = 2.5-3.0 cmH2O), and the
tail vein was cannulated with a 27-gauge needle for injection of the
methacholine challenge. The plethysmograph was sealed, and readings
were monitored by computer. Because the box was a closed system, a
change in lung volume was represented by a change in box pressure
(Pbox) that was measured by a differential transducer. The
system was calibrated with a syringe that delivered a known volume of 2 ml. A second transducer was used to measure the pressure swings
at the opening of the tracheal tube (Paw) referenced to the body
box (i.e., pleural pressure) and to provide a measure of transpulmonary
pressure (Ptp = Paw
Pbox). The tracheal transducer was calibrated at a constant pressure of 20 cmH2O. Resistance was calculated with Buxco software by
dividing the change in pressure (
Ptp) by the change in flow (
F;
box pressure;
Ptp/
F in
cmH2O · ml
1 · s
1)
at two time points from the volume curve based on a percentage of the
inspiratory volume. Once the mouse was hooked up to the box, it
was ventilated for 5 min before readings were acquired. Once
baseline levels were stabilized and initial readings were taken, a
methacholine challenge was given via the cannulated tail vein. After
the determination of a dose-response curve (0.001-0.5 mg), an
optimal dose of 0.1 mg of methacholine was chosen. This dose was used
throughout the rest of the experiments in this study. After the
methacholine challenge, the response was monitored, and the peak airway
resistance was recorded as a measure of airway hyperreactivity.
Collection of BAL fluid.
Lungs from mice were perfused with 1 ml of PBS via intratracheal
injection with a 1-ml syringe and a 26-gauge needle. After 30-40
s, the PBS was collected by aspiration with the same syringe and
needle. Between 700 and 800 µl could routinely be re-collected from
the perfused lung. The cells were then collected by centrifugation, resuspended in fresh PBS, and cytospun onto a glass slide. The cytospins were then differentially stained with eosin and hematoxylin. The percentage of cells was then determined by counting the number of
eosinophils per 200 total cells. Histamine levels were measured in
cell-free BAL fluid by ELISA with commercially available kits (Amac,
Westbrook, MA). Leukotrienes (LTs) from the BAL fluid were assessed
with enzyme immunoassay kits (Cayman Chemical, Ann Arbor, MI).
Cytokine analysis by ELISA.
The levels of TNF-
in BAL fluid were measured by specific ELISA with
a modification of a double-ligand method as previously described
(6). Briefly, lung tissue was homogenized on ice with a
tissue tearor (Biospec Products, Racine, WI) for 30 s in 1 ml of
PBS containing 0.05% Triton X-100. The resulting supernatant was
isolated after centrifugation (10,000 g). Flat-bottom,
96-well microtiter plates (Nunc, Roskilde, Denmark) were coated with 50 µl/well of rabbit polyclonal antibodies specific for the cytokine or
chemokine in question for 16 h at 4°C and then washed with PBS
and 0.05% Tween 20. Nonspecific binding sites were blocked with 2%
BSA in PBS and incubated for 90 min at 37°C. Plates were rinsed four
times with wash buffer, and cell-free supernatants were added (neat and
diluted 1:10) followed by incubation for 1 h at 37°C. Plates
were washed four times, streptavidin-peroxidase conjugate (Bio-Rad,
Richmond, CA) was added, and the plates were incubated for 30 min at
37°C. Plates were washed again, and chromogen substrate (Bio-Rad) was
added and incubated at room temperature to the desired extinction. The
reaction was terminated with 50 µl/well of 3 M
H2SO4 solution, and the plates were read at 490 nm in an ELISA reader. Standards were 0.5 log dilutions of recombinant protein from 1 pg/ml to 100 ng/ml.
Statistical analysis.
Significance was determined by ANOVA, with P values < 0.05.
 |
RESULTS |
IgG immune complex-induced, complement-dependent airway
hyperreactivity.
Intrapulmonary deposition of IgG immune complexes can result in injury,
including a vascular leak syndrome, significant recruitment and
activation of neutrophils, and damage to lung tissue. To determine whether this complement-dependent inflammatory response had a pathophysiological consequence, we examined lung function parameters in
mice with IgG immune complex-induced injury in the lung. Mice were
injected intratracheally with anti-BSA IgG followed by the intravenous
injection of BSA (1 mg). As shown in Fig.
1, the induction of airway
hyperreactivity to a methacholine challenge was most severe by 1 h, was still apparent but diminishing by 4 h, and had resolved by
24 h postimmune complex deposition. Control mice given
intratracheal antibody with saline challenge instead of BSA showed no
significant increase in airway resistance. These data demonstrated an
early response to IgG immune complexes that was characterized by
increased airway resistance. Histological changes in the lungs
indicated interstitial and intra-alveolar accumulations of neutrophils
and were associated with the airway hyperreactivity
changes observed (Fig. 2).
Because the immune complex-induced inflammation has been shown to be a
complement-mediated pathway, we examined mice that had been complement
depleted. This was accomplished with an injection of CVF 18 h
before induction of the immune complex-induced response. The
histological results indicated reduced inflammation in the
complement-depleted animals after immune complex deposition (Fig.
2C), whereas in complement-intact mice, a marked neutrophil
infiltration was detected in the bronchial wall (Fig.
2, B and D). The data presented in Fig.
3 clearly demonstrate that when
complement was inhibited by pretreatment with CVF, the airway
hyperreactivity response was nearly abolished. These results are
consistent with previous data (21, 43, 57) that
indicated that the immune complex-induced airway responses require
complement-mediated activation events and suggest that airway
hyperreactivity requires at least C3.

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Fig. 1.
Immune complex-induced pulmonary inflammation mediated
airway hyperreactivity. Mice were given intratracheal injections of
anti-BSA (50 µg/mouse) and challenged with intravenous BSA (1 mg).
The mice were subsequently examined for airway hyperreactivity
responses after an intravenous injection of methacholine (100 µg/kg).
Data are means ± SE from 5-6 mice/group and represent the
change in airway resistance over background levels.
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Fig. 2.
Histological examination of immune complex-induced
inflammation inhibited by cobra venom factor (CVF). Animals were given
CVF (200 U/kg) and challenged with immune complex-induced inflammation
the next morning. Normal animals (A) were used for
comparison, and complement-depleted animals (C) demonstrated
substantially less inflammation compared with control immune
complex-challenged mice (B and D). Arrow,
neutrophils; arrowhead, edema or leak from the inflammatory
response.
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Fig. 3.
Complement depletion blocked the immune complex induction
of airway hyperreactivity. Animals were given CVF (200 U/kg) and
challenged with immune complex-induced inflammation the next morning.
The mice were subsequently examined for airway hyperreactivity
responses after an intravenous injection of methacholine (100 µg/kg)
4 h after immune complex challenge. Bkgd, background. Data are
means ± SE from 5-6 mice/group and represent the change in
airway resistance over background levels. * P < 0.05 compared with BSA/anti-BSA positive control.
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To further define the complement products that may be responsible for
the responses during intrapulmonary immune complex deposition, we
treated the challenged mice with specific anti-C5a antibody given intratracheally. The data in Fig.
4 indicate that the blockade of
C5a significantly attenuated airway hyperreactivity responses. We
examined the neutrophil recruitment responses and found a decrease in
the anti-C5a-treated mice compared with the control mice at 4 h
postdeposition (12.6 ± 2.0 × 104 and 18.8 ± 1.8 × 104/ml, respectively; n = 5/group). Thus the immune complex-induced airway hyperreactivity is
dependent on the activity of the complement, specifically, C5a.

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Fig. 4.
Blockade of C5a decreased induction of airway
hyperreactivity. Antibodies specific for C5a (50 µg/mouse) were
injected intratracheally along with the anti-BSA during the immune
complex challenge. The mice were subsequently examined for airway
hyperreactivity responses after an intravenous injection of
methacholine (100 µg/kg). Data are means ± SE from 5-6
mice/group and represent the change in airway resistance over
background levels. * P < 0.05 compared with BSA/anti-BSA
positive control.
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Association of airway hyperreactivity with TNF-
and histamine.
Because the early time point (1 h) showed peak airway hyperreactivity,
we examined common cytokine pathways. TNF was significantly reduced
after CVF-mediated complement depletion 1 h postchallenge (Fig.
5). Measurement of histamine levels in
the BAL fluid demonstrated that the mediator was released into the
airways 1 and 4 h postchallenge (Fig.
6), producing levels of 8-10 and
25-30 nM, respectively. When animals were complement depleted,
significantly less histamine was detected in the BAL fluid; at 1 and
4 h, the level was <1 nM. When LTE4 was examined,
there was a significant increase in its levels in BAL fluid 1 h
after the immune complex response compared with that in control animals
(412 ± 112 and <10 pg/ml, respectively). However, no significant
decrease in LTE4 was observed after CVF treatment (422 ± 116 pg/ml). Thus at least two important mediators were significantly
affected by depletion of complement before immune complex-induced
inflammation, whereas levels of LTE4 were unaffected.

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Fig. 5.
CVF blockade of complement inhibited tumor necrosis
factor (TNF) production during immune complex-induced airway
hyperreactivity. A 1-ml bronchoalveolar (BAL) fluid sample was
harvested from each mouse 1 h postchallenge, and the level of TNF
was assayed by specific ELISA. Data represent results from 5 different
mice/group. * P < 0.05.
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Fig. 6.
Immune complex-mediated inflammation induced histamine
release that is dependent on complement. Animals were given CVF (200 U/kg) and challenged with immune complex-induced inflammation the next
morning. Histamine levels were measured in cell-free BAL fluid
collected from individual mice. Data represent means ± SE from
5-6 mice/group. * P < 0.05 compared with control.
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Airway hyperreactivity in C5-deficient mice.
We examined immune complex-induced inflammation in C5-deficient mice
compared with congenic C5-sufficient mice. As shown in Fig.
7, airway hyperreactivity in C5-deficient
mice was similar to that in the C5-sufficient mice. The data indicated
that the responses in the B10 strain of mice shown in Fig. 7 were lower compared with those observed in the CBA/J strain (Fig. 1), making comparisons between strains somewhat problematic. In these same studies, complement depletion was carried out with an overnight treatment with CVF. Induced complement depletion treatment
significantly lowered airway hyperreactivity responses in C5-sufficient
mice, whereas the C5-deficient mice pretreated with CVF showed no
significant decrease (Fig. 7). These data suggested that mechanisms
other than CVF-sensitive products were operative in the C5-deficient mice for the induction of airway hyperreactivity. To correlate these
results with previous observations in Association of airway hyperreactivity with TNF-
and histamine, we also examined
histamine levels in the BAL fluids of these mice (Fig.
8). The C5-deficient mice demonstrated a
lower level of histamine in the BAL fluid compared with the
C5-sufficient mice after immune complex responses. CVF treatment of
C5-sufficient animals virtually abrogated the increase in histamine
content in the BAL fluid, whereas CVF treatment only partially
attenuated histamine release in the BAL fluid of C5-deficient mice.
These results partially correlate with the airway hyperreactivity data.
Collectively, the data suggest that IgG immune complex-induced airway
hyperreactivity is C3, C5, and C5a dependent. Increases in BAL fluid
levels of TNF and histamine (but not of LTE4) are
complement dependent. In C5-deficient mice, there appears to be some C3
dependency, but other mediator pathways, such as Fc
, have been
engaged.

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Fig. 7.
Immune complex-induced pulmonary inflammation induced
airway hyperreactivity in C5-deficient mice that is not blocked by CVF
treatment. C5-sufficient and -deficient animals were given CVF, and
18 h later, an immune complex challenge followed by examination of
the airway hyperreactivity response to methacholine. Data are
means ± SE from 7-8 mice/group. * P < 0.05 compared with BSA.
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Fig. 8.
Histamine levels in the airway of C5-deficient mice were
not completely blocked by complement depletion with CVF. Histamine
levels were measured from cell-free BAL fluid collected in individual
mice 4 h after immune complex challenge. Data are means ± SE
from 7-8 mice/group.
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 |
DISCUSSION |
Bronchial asthma is a disorder associated with airway inflammation
and characterized pathophysiologically by airway hyperreactivity that
is induced by a variety of stimuli (5, 15, 32, 46, 59,
64). Classically, asthmatic responses have been related to
IgE-mediated pathways that induce mast cell and basophil activation and
degranulation that lead to mediator release. In these present studies,
we have demonstrated that IgG immune complex deposition in the lung can
induce severe airway hyperreactivity in the mouse, a finding that has
not been previously reported. The extensive body of information related
to the pathophysiological mechanisms involved in this model of lung
injury has allowed us to obtain further information on events that are
triggered by tissue deposition of IgG immune complexes. These reactions
are accompanied by TNF-
production, histamine release, and
neutrophil accumulation. The hyperreactivity response peaked early (by
1 h) and had resolved by 24 h. Interestingly, the airway
permeability observed in this model had previously been shown to peak
at 4 h (42, 43, 63), suggesting that the
hyperreactivity may be a related but separate event. Previous
studies (21, 43, 57) have clearly demonstrated that this inflammatory response is dependent on complement activation products. Depletion of complement by CVF inhibited the development of
airway hyperreactivity.
The complement activation products C3a and C5a (anaphylatoxins) are
known to produce airway smooth muscle constriction in guinea pigs and
humans (48, 54, 55, 60). C3a and C5a receptors have been
found on eosinophils, basophils, mast cells, monocytes, neutrophils,
activated lymphocytes, and numerous nonmyeloid cell populations
(21, 22). Anaphylatoxins can cause histamine and mediator
release from basophils and mast cells (23, 25, 28, 31, 53, 65,
66). In addition, C5a is a chemotactic and activating factor for
effector cells such as neutrophils and eosinophils (29, 36, 45,
57, 61). Finally, C3a and C5a have been shown to upregulate the
expression of selectins and
2-integrin molecules
(2, 30, 35, 41, 42). Endothelial cells respond directly to
C5a with increased expression of P-selectin on their surfaces. In the
present studies, it appears that complement activation products lead to
stimulation of mast cell/basophil populations, resulting in the release
of histamine, LTE4, and other acute mediators. TNF-
,
which can be readily released from mast cells, was also affected by
depletion of the complement. Because histamine levels were more
elevated at 4 h compared with 1 h, it is possible that multiple factors and cell populations are involved in the progression of the airway hyperreactivity responses. Taken together, these studies
suggest a significant role for complement activation in the lung that
leads to alteration of lung function.
CVF (cobra C3b) is known to bind to factor B of the alternative
complement pathway, forming a stable C3bBb complex and a markedly depleted C3, resulting in blockade of all three complement pathways (3, 12, 13, 44). Pretreatment of mice with CVF to inhibit complement-mediated pathways attenuates the immune complex-induced response within the lung. After CVF injection, the hyperreactivity response to the bronchospastic mediator methacholine was nearly completely attenuated. This was further supported by the histopathology in mice treated with CVF, which demonstrated decreased injury, inflammation, and reduced airway changes. In addition, the depletion of
C5a with specific antisera further suggests that this complement component is one of the key factors involved in the development of
airway hyperreactivity with this model. The data in this report demonstrate that complement may be an essential pathway in the hyperreactive airway response.
In an attempt to examine the requirements for specific complement
components, we used congenic mice that were either deficient or
sufficient in C5. Although there were some differences between the two
groups in their hyperreactive airway responses, the differences were
not significant. However, when these animals were complement depleted
with CVF, a distinct difference was observed. As noted above, treatment
with CVF attenuated the hyperreactivity response and reduced histamine
levels in C5-sufficient but, surprisingly, not in C5-deficient mice.
These results suggest that although C3 and C5 play an important role in
the responses to immune complexes in complement-intact mice, other
pathways appear to compensate for the absence of C5. It remains to be
determined how this compensation occurs, but it may involve several
other mediator pathways (1, 33, 58). Anti-C5a treatment
significantly blocked the airway hyperreactivity in C5-intact mice,
suggesting that this component plays a significant role in the
development of the responses. This is in keeping with recently
published results of a study (16) that used anti-C5a
antibody for the treatment of acute septic responses. The
connection between mast cell/basophil activation and airway
hyperreactivity is well accepted. Taken together, these studies connect
the interacting effects of complement activation, mast cell/basophil
degranulation, and early-phase airway hyperreactivity, at
least in complement-intact mice.
The bronchoconstrictive responses observed in asthma are multifactorial
and are triggered by numerous factors including allergens, cold air,
exercise, pollutants, and viral infections (19,
38-40). Thus it is not surprising that multiple mediators
are involved in pathophysiological responses during the evolution of
bronchospastic disease. The results from these studies indicate that
bronchospastic mediators that may be common to allergen-induced
responses are also produced during an immune complex-induced response.
Histamine and leukotrienes (LTC4, LTE4) as well
as TNF-
are produced at significant levels within the airway during
the immune complex response. Although the exact source of these
mediators was not identified in these studies, all of these can be
produced by mast cell/basophil populations within the lung. Other cell
populations, such as epithelial cells and recruited inflammatory cell
populations, have the ability to produce leukotrienes (4, 20,
51). Interestingly, the C5-deficient mouse studies indicated
that immune complex-induced airway hyperreactivity is not completely
dependent on this pathway. Fc
receptors are also relevant and may be
important in the airway hyperreactivity response. Several studies
(14, 24, 56) have indicated that local lung populations
may be a source of complement proteins relevant in this injury. In a
global sense, this model demonstrates that both complement-dependent
and complement-independent pathways may be relevant in acute bronchial
hyperreactivity responses induced by IgG immune complexes. Whether
these responses translate directly to human asthma needs to be
considered and is worthy of further investigation.
 |
FOOTNOTES |
Address for reprint requests and other correspondence: N. W. Lukacs, Univ. of Michigan Medical School, Dept. of Pathology, 1301 Catherine, Ann Arbor, MI 48109-0602 (E-mail:
nlukacs{at}umich.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.
Received 15 July 1999; accepted in final form 16 October 2000.
 |
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