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,§
,§,§,§
*
Division of Pulmonary and Critical Care Medicine and
Division of Oncology, Department of Medicine, and
Department of Pathology, University of Washington, Seattle, WA 98195; and
§
Fred Hutchinson Cancer Research Center, Seattle, WA 98109
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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in culture, whereas TNF- was not detected in AM cultures
from control mice. TNF- production in response to LPS stimulation
was significantly higher in AM cultures derived from T cell-treated
mice than in those from control mice. Challenge with sublethal doses of
LPS resulted in 50% mortality in T cell-treated mice and was
associated with augmented AM TNF- production and protein in
bronchoalveolar lavage fluid. We conclude that immune activation of T
cells of the Th1 phenotype can initiate lung injury characterized by a
host-derived mononuclear cell inflammation and activation of
AM. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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production, whereas Th2 cells are
characterized by IL-4, IL-5, and IL-10 production. Th1 cells are
strongly associated with T cell-mediated proinflammatory responses. Studies of cytokine expression in murine models of acute GVHD as well as in humans undergoing allogenic marrow transplantation have implicated Th1-type responses in the generation of severe GVHD (11, 12). Direct evidence of a role for Th1 cells derives from the demonstration that in vitro generated alloreactive CD4+ T cells of the Th1 type result in the acute lethality characteristic of GVHD (weight loss and diarrhea) in a murine transplant model (11). Moreover, Lehmann et al. have reported that cloned alloreactive Th1 cells administered to untransplanted mice resulted in lung and liver toxicity characterized by vascular leak (15).
While donor T lymphocytes are essential for the initiation of GVHD, the pathologic consequences may be mediated by distal non-T cell immune cells of the monocyte/macrophage lineage. Nestel and colleagues (16) have recently provided experimental evidence for this mechanism, advancing the concept that immune-activated macrophages are important effector cells in murine GVHD. Although this mechanism has not been directly studied in lung, lung injury associated with GVHD in murine marrow transplant models has been previously described (17, 18, 19), and Th1-like responses have been suggested as a possible effector mechanism (20).
We recently provided direct evidence for a Th1-mediated mechanism of
acute lung injury in a murine model induced by alloreactive Th1 cell
clones that recognize Ly5 (CD45), a polymorphic cell surface
glycoprotein expressed on hemopoietic cells (21). In mice, two
Ly5 alleles (Ly5a, which encodes the
Ly5.1 cell surface molecule, and Ly5b, which encodes
the Ly5.2 cell surface molecule) have been defined. Alloreactive cloned
T cells, specific for host Ly5 Ag, caused a mononuclear cell
pulmonary vasculitis and interstitial
pneumonitis.4 At high T cell
doses, lethal pulmonary hemorrhage was observed. The only other notable
organ involvement was hepatic vasculitis. In vitro studies established
that the cloned T cells were not cytolytic, and after stimulation with
allogenic splenocytes or specific Ly5 peptide, they produced
IFN-, but not IL-2, IL-4, or IL-10.
The apparently selective lung injury lead us to question whether Ly5 might be expressed in lung parenchymal cells as well as hemopoietic cells. To test this, we created chimeras by transplantation of Ly5b marrow into irradiated Ly5a mice (21). Lung injury was induced by anti-Ly5b T cells but not by anti-Ly5a cells, indicating that allogeneic hemopoietic cells provide sufficient stimulation for eliciting lung injury. Thus, lung injury initiated by an allogeneic immune effector cell does not require T cell recognition of a specific Ag in lung parenchyma.
These observations prompted us to investigate further the mechanisms by which alloreactive T cell activation can lead to inflammatory lung injury. In this report we present evidence that immune activation of T cells of the Th1 phenotype initiates an inflammatory reaction in lung that is amplified by host-derived mononuclear cells, characterized by activation of alveolar macrophages (AM), and associated with greatly increased susceptibility to sublethal LPS challenge.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6, Ly5a, RAG-1-deficient (22), and lacZ transgenic (23) mice were obtained from The Jackson Laboratory (Bar Harbor, ME). Some Ly5a mice were bred at the Fred Hutchinson Cancer Research Center (Seattle, WA). Mice were housed in microisolator cages under specific pathogen-free conditions with free access to sterile chow and water.
T cell clones and culture
T cell clones specific for Ly5a (clone 8F5)
and Ly5b (clone 1A4) alleles were developed and
maintained in culture as previously described. In brief,
Ly5b mice and congenic Ly5a mice
were cross-immunized with 13 mer Ly5a and
Ly5b peptides identical with a polymorphic region
(p257–269) differing by three amino acids. CD4+ Th cells
specific for the 13 mer peptides were elicited and cloned by limiting
dilution. The clones used in these studies were 1A4 (specific for
Ly5b) and 8F5 (specific for Ly5a)
(21). Both were of the Th1 phenotype and produced IFN-. One of the
clones selected for study (1A4) did not produce IL-2. In previous
studies no qualitative differences in biologic activity (i.e.,
induction of lung injury) were detected. T cell clones were expanded by
periodic stimulation with peptide (Ly5a) or
allogeneic irradiated splenocytes in the presence of congenic
irradiated splenocytes (allogenic to congeneic cells in a ratio of
1:10) and were maintained in the presence of IL-2 (10 U/ml).
In one experiment, T cells were stimulated and maintained for 2 wk in the presence of 100 µM bromodeoxyuridine (BrdUrd; Boehringer Mannheim, Indianapolis, IN).
Induction of lung injury
Cloned T cells (5, 7.5, or 10 x 106 cells in 0.5 ml of sterile PBS) were injected i.v. into the lateral tail vein of recipient mice. Resting T cells had undergone in vitro stimulation 2 to 3 wk before transfer into mice. Stimulated T cells were stimulated in vitro with allogeneic splenocytes 24 h before transfer into mice. In one experiment, T cells were stimulated by incubation for 24 h in wells precoated with Ab to CD3 (clone 145-2c11, PharMingen, San Diego, CA).
In some experiments, LPS (Escherichia coli 0111:B4, List Laboratories, Campbell, CA) was administered i.p. to mice 24 h after T cell transfer at a dose of 5 mg/kg. This dose (100 µg of LPS in a 20-g mouse) was estimated to be 20% of a lethal dose of LPS in B6 mice (24).
Histology
Mice were anesthetized with Avertin (Aldrich, Metuchen, NJ) and exsanguinated by renal artery transection. For histopathologic evaluation, lungs were excised at various times after T cell transfer, inflated at 25-cm H2O pressure with 10% formalin, fixed overnight, embedded in paraffin, sectioned, and stained with hematoxylin and eosin. The histopathology was scored (0–4+) according to the extent and severity of vasculitis and inflammatory cell infiltration as follows: 0 = no abnormality; 1+ = minimal inflammation involving <10% of venules; 2+ = mild vasculitis involving 10 to 25% of venules; 3+ = moderate vasculitis and perivascular inflammation involving >25% of venules; and 4+ = severe vasculitis and perivasculitis with alveolar and interstitial inflammation. All slides were coded and read by a pathologist without knowledge of the experimental treatment.
For immunohistochemical detection of T cells, excised lungs were inflated and embedded in Tissue-Tek OCT compound (Cryoform, IFC, Needham Heights, MA), snap-frozen in liquid nitrogen, and stored at -70°C. Cryosections were fixed in acetone and stained with Ab to CD3e (clone 145-2C11, PharMingen). Ab was detected with biotinylated goat anti-hamster Ig followed by streptavidin-peroxidase complex and then diaminobenzidine and NiCl2. Primary Ab was omitted in control sections. Sections were counterstained with acridine orange/safronin O. Control tissue included normal mouse spleen.
For immunohistochemical detection of BrdUrd-labeled T cells, excised lungs were inflated, fixed in fresh 4% paraformaldehyde, and embedded in paraffin. Sections were incubated in proteinase K solution and then in 4 N HCl. BrdUrd was detected with an alkaline phosphatase-conjugated mouse mAb, F(ab')2, and Fast Red substrate according to the manufacturer’s directions using an in situ cell proliferation kit (AP, Boehringer Mannheim, Indianapolis, IN). Sections were counterstained with hematoxylin. In control slides, mAb was omitted. A cytocentrifugation preparation of the BrdUrd-labeled T cells was fixed in 4% paraformaldehyde, air-dried, and immunostained as described for the tissue sections. Control tissues included lung from a normal mouse and testes from a mouse that received BrdUrd in vivo.
For detection of bacterial ß-galactosidase activity, lungs were excised from C57BL/6 mice and ROSA-26 transgenic mice that constitutively express the lacZ gene (23). The procedure for in situ ß-galactosidase activity in whole lung has been described in detail previously (25). In brief, lungs were fixed by inflation with 1% glutaraldehyde for 60 min. Fixative was removed by aspiration, and the airways were rinsed with PBS. A solution containing 0.2% X-galactosidase (Sigma), 5 mM potassium ferriferrocyanide, 2 mM MgCl2, and 100 mM Tris-base, pH 8.0, was instilled into the trachea at 30-cm H2O pressure. The inflated lungs were immersed in X-galactosidase solution overnight at 37°C. The X-galactosidase solution was then aspirated. The lungs were fixed in 10% formalin and embedded in paraffin as described above. Deparaffinized sections were stained with nuclear Fast Red.
In preliminary studies we determined that endogenous (mammalian) ß-galactosidase activity was not detected under these staining conditions in either the T cell clone (8F5) 24 h after in vitro stimulation or in lung or spleen from C57BL/6 mice, but ß-galactosidase activity was readily detected in lung and spleen of the transgenic mice.
Bronchoalveolar lavage (BAL) and AM culture
Mice were anesthetized with Avertin and exsanguinated by renal
artery transection. The thorax was opened by a midline sternotomy, and
the trachea was exposed by a midline incision and cannulated with a
polypropylene catheter. The lungs were lavaged with 1.5-ml aliquots of
sterile Ca2+- and Mg2+-deficient PBS
supplemented with 0.6 mM EDTA. The first milliliter of BAL was placed
in a separate tube and centrifuged at 500 x g to
remove cells. The BAL supernatant was frozen at -70°C for analysis
of IFN-, TNF-, and protein (26). The next 10 ml of lavage fluid
was centrifuged to recover cells. The cell pellet was combined with the
cell pellet from the first milliliter in cold HBSS, centrifuged, and
resuspended in 1 ml of HBSS. Cells from control or experimental animals
(n = 3 or 6) were pooled and counted using trypan blue
exclusion as a measure of viability. Differential cell counts were
performed on Wright-stained cytocentrifuge preparations. More than 95%
of the cells were AM. Cells were again centrifuged and resuspended at a
concentration of 2 x 106 cells/ml in RPMI with 5%
glucose, 100 U/ml penicillin, and 100 µg/ml streptomycin. The cells
were plated in 96-well culture dishes and cultured at 37°C in a 5%
CO2 atmosphere for 60 min. Nonadherent cells and media were
removed, and adherent cells were washed once with HBSS. Adherent cells
were then incubated in RPMI with 5% glucose, 100 U/ml penicillin, 100
µg/ml streptomycin, and 5% FCS. In some experiments, LPS (E.
coli 0111:B4, List Laboratories, Campbell, CA) at different
concentrations was added to the cultures. The culture medium was
removed after 24 h for analysis of TNF-.
Cytokine determination
IFN- was measured using a specific murine ELISA kit from
Endogen (Woburn, MA). TNF- was measured using a specific murine
ELISA kit from Genzyme (Cambridge, MA).
Statistical analysis
Comparisons among experimental groups were analyzed by one-way analysis of variance testing and Tukey’s multiple comparison method, using SPSS/PC+ statistical software (SPSS, Chicago, IL).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We previously showed that in vitro activation of
Ly5a-specific or Ly5b-specific T
cell clones required presentation of Ly5a or
Ly5b Ag, respectively. Similarly,
Ly5a-specific clones induced lung injury in vivo in
Ly5a mice, but not Ly5b mice, and
vice versa (21). To determine whether continuous specific Ag
presentation and T cell clone activation and proliferation were
required for the development and progression of lung injury, we
stimulated Ly5a-specific T cells in vitro with
Ly5a peptide and congenic splenocytes. Resting or
stimulated Ly5a-specific T cells (5 x
106 cells) were administered i.v. to
Ly5a or Ly5b mice, and lung
histopathology was evaluated 1, 3, and 6 days later. As shown in Table I
, the administration of resting
anti-Ly5a T cells resulted in lung injury to
Ly5a mice, but not Ly5b mice, but
stimulated anti-Ly5a T cells caused lung injury
in both Ly5a and Ly5b mice. The
extent of involvement, based on semiquantitative histopathology score,
was similar throughout the period of observation. Moreover, the
evolving histopathologic features were similar in all affected mice
(Fig. 1). Similar results were obtained
with T cells that were stimulated in vitro with Ab to CD3 for 24 h
before adoptive transfer in vivo (data not shown). As previously shown
in the chimera experiments, these results indicate that Ag localization
in lung is not required (i.e., a lung-specific target). These results
also suggest that the initial activation of the T cell clone promotes a
sustained bystander inflammatory injury in lung.
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Immunohistochemical identification of T cells. Lung tissue for frozen sections was obtained from C57BL/6 (Ly5b) mice 1 day after transfer of 5 x 106 resting anti-Ly5b T cells. By immunohistochemistry, a subpopulation of cells in the mononuclear inflammatory cell reaction around vessels was lightly stained by a T cell Ab (not shown). We estimated that approximately 20% of the cells were CD3e positive. Lymphocytes in control spleen tissue were strongly positive.
In vitro BrdUrd-labeled T cells.
To determine whether the T cells in lung were derived from the cloned T
cells, we labeled the anti-Ly5b T cells in vitro
with BrdUrd (100 µM) before transfer to Ly5b mice.
By immunohistochemistry, BrdUrd-labeled cells were detected in the
vascular inflammatory foci 1, 2, 3, and 7 days after transfer of the T
cells (Fig. 2), but not in normal lung
from control animals. Rare labeled cells were seen in apparently normal
areas of lung from T cell-treated mice. It appeared that the number of
labeled T cells decreased over time. This could result from either T
cell disappearance (death) or loss of label. These results suggest that
Th1 cell localization in lung is involved in the initial steps of the
inflammatory response.
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) was present in
both control Ly5b mice and mutant
RAG-1-deficient mice. Semiquantitative pathologic scoring of
the lesions, performed in a blinded manner, indicated no difference
between control and mutant mice at any of the time intervals tested
(Table II). These results indicate that
host-derived T or B cells are not required for the clone-induced
inflammatory reaction in lung.
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). Consistent with the BrdUrd
data, some (20–30%) ß-galactosidase-negative inflammatory cells
(presumably T cells) were present at 1 day. No ß-galactosidase
activity was detected in the lungs of control mice that had been
similarly treated or in cytospin slides of activated cloned T cells.
The results of these experiments collectively suggest that the lung
inflammatory response initiated by Th1 cells is amplified by recipient
mononuclear cells.
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and TNF- in BAL 24 h after i.v. transfer of 5 x
106 Ly5b-specific T cells (clone 1A4) to
Ly5b mice. Neither IFN- nor TNF- was detected
in control mice, while in T cell-treated mice, BAL contained both
TNF- (mean ± SD, 29 ± 8 pg/ml; n = 6)
and IFN- (2287 ± 752 pg/ml; n = 3). After 48
or 72 h, IFN- and TNF- were not consistently detectable in
BAL.
To determine whether the histopathologic inflammatory response was
associated with vascular leak, we measured total protein in BAL at
intervals after the administration of 107Ly5b-specific T cells to
Ly5b mice. As shown in a representative experiment
(Table III), total protein was
significantly increased 24 h after T cell administration and
remained elevated at 72 h.
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in vitro. Twenty-four hours after transfer of
anti-Ly5b T cells (5 x 106),
AM from treated and control Ly5b mice
(n = 6 in each group) were obtained and cultured in
parallel for 24 h. Conditioned medium from the AM cultures was
assayed by ELISA for in vitro release of TNF- (Fig. 4). AM lavaged from control animals did
not release detectable TNF- in the absence of LPS, whereas AM
lavaged from T cell-treated mice spontaneously released TNF-.
Addition of LPS to cultured AM from control mice stimulated release of
TNF- into the culture supernatants. In mice given T cells, the
capacity of AM to release TNF- in response to LPS stimulation was
increased two- to threefold.
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In another similar experiment, Ly5b mice
(n = 3) were similarly challenged with
anti-Ly5b T cells (107 cells)
followed by LPS. Control mice (n = 3 in each group)
received no treatment, T cells only, or LPS only. Twenty-four hours
after LPS, mice were lavaged for analysis of BAL protein and cultures
of AM. After 24 h in culture, TNF- levels in the AM culture
media were measured (Fig. 5). TNF-
production by AM from mice that received T cells or LPS only was
significantly increased compared with that in untreated controls
(p < 0.01). However, even higher TNF-
production was observed in AM from mice that received T cells followed
by LPS challenge (p < 0.01). Similarly, BAL
protein was mildly increased (not significantly) in mice treated with
either T cells or LPS alone, whereas mice that received T cells
followed by LPS challenge had substantially increased BAL protein
concentration (p < 0.05) (Fig. 6). Thus, increased susceptibility to
sublethal LPS challenge after Th1 cell activation is associated with
increased AM TNF- production and lung protein leak into alveoli.
Even though the increased mortality under these conditions may not be
directly related to the lung, an enhanced macrophage inflammatory
response to LPS may be an important mechanism of lung injury in the
setting of immune cell activation.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. In addition, Th1 cell-mediated lung injury results
in greatly increased susceptibility to sublethal LPS challenge, with
associated increases in AM production of TNF- and increases in BAL
protein.
IFN-, the defining proinflammatory cytokine produced by Th1 cells,
has been implicated in the pathogenesis of GVHD. Serum levels are
increased in patients and in murine GVHD (27, 28, 29). IFN- mRNA is
increased in target organs, including the lung in murine GVHD (30). In
our experiments, Th1 clone cells were present selectively in
inflammatory foci in lung, and IFN- was increased in BAL fluid after
Th1 cell administration. Prominent among the effects of IFN- is the
activation of macrophages to secrete cytokines such as TNF- (31, 32). In our model, AM from Th1 cell-treated mice spontaneously secreted
TNF- in vitro, and TNF- levels were increased in BAL. Similar
spontaneous TNF- production by peritoneal macrophages has been
reported in murine GVHD and has been attributed to IFN-, although a
causal role has yet to be directly established (16). Other T
cell-derived cytokines, such as IL-2, macrophage inflammatory
factor, and TNF-ß might also play an important activating
role, having potentially overlapping function with IFN- (32).
While Th1 cells and their cytokine products may be critical in initiating an inflammatory response in lung, our experiments in lacZ transgenic mice indicate that the inflammatory cell population is comprised largely of host-derived cells. A similar preponderance of recipient-derived cells has been shown in lung and other target organs in an unirradiated murine GVHD model induced by transfer of CD3 cells (33). Host-derived macrophages were also increased in lungs of irradiated mice with GVHD (29). Our experiments in RAG-1-deficient transgenic mice, which lack T and B cells, showed that the inflammatory response to Th1 cell administration was not diminished in these mice. This result suggests that monocytes are a major component within the inflammatory cell population. The mechanisms involved in inflammatory cell recruitment to lung are not known, but the striking localization of mononuclear cells in the pulmonary vasculature strongly suggests that vascular adhesion molecules are up-regulated during the development of Th1 cell-induced lung injury. The exclusively mononuclear cell inflammatory response points to a possible role for VCAM-1.
Both in vitro experimental data and animal studies suggest that VCAM-1
may be of particular relevance in our model (34, 35, 36). VCAM-1 is a
member of the Ig supergene family of cellular adhesion molecules
expressed on vascular endothelial cells and is induced by
proinflammatory cytokines such as IL-1 and TNF- (37). Cell adhesion
to VCAM-1 is mediated by the integrin 4ß1
(very late Ag-4), which is expressed on most mononuclear cells but not
neutrophils. Other studies of animal models of immune and inflammatory
disease suggested that the 4 integrin-dependent pathway
plays a central role (35).
The selective recruitment of mononuclear cells may be further refined by localized expression of chemotactic molecules. Recently, a superfamily of proinflammatory cytokines with chemotactic activity has been characterized (38, 39). The ß-chemokine family, also known as C-C chemokines, attract primarily monocytes and T lymphocytes (40). C-C chemokines are produced by T lymphocytes as well as a variety of other cell types, including endothelial cells, macrophages, and airway epithelial cells (39, 40, 41, 42). C-C cytokine production is stimulated by proinflammatory cytokines (43). In addition to their chemotactic activity, C-C cytokines are now known to modulate cytokine production and adhesion molecule expression (44, 45). Clearly, this family of C-C chemokines, by virtue of selective cell recruitment and their stimulatory activity, could function in conjunction with vascular adhesion molecules and integrins as important modulators of inflammatory responses such as that observed in our model.
An important emerging theme is that while donor T cells are essential
for the generation of GVHD, the pathology may be in large part mediated
by distal, non-T cell immune processes, such as the secretion of
multiple inflammatory products from cells of monocyte/macrophage
lineage (11, 12, 43). In our experiments, TNF- was spontaneously
secreted by AM after Th1 cell administration. TNF- is directly
cytotoxic and also mediates a wide variety of proinflammatory effects,
including activation of leukocytes to produce other proinflammatory
cytokines, such as IL-1, IL-6, IL-8, and TNF- itself. TNF- also
has been implicated as an important cytokine in inflammatory lung
injury models (39).
Alloreactive T cell activation, mononuclear cell recruitment to lung,
and monocyte/macrophage activation appear to be important component
mechanisms in the pathogenesis of lung injury in our experiments.
Tissue injury may be further exacerbated by environmental challenges
such as LPS in susceptible mice. Our experiments showed that
susceptibility to sublethal doses of LPS was greatly increased after
Th1 cell administration. The LPS challenge in Th1 cell-treated mice was
associated with increased AM production of TNF-, increased BAL
protein leak, and increased mortality. Others have shown that
proinflammatory cytokines such as IFN- increase susceptibility to
LPS (46).
Others have proposed that gastrointestinal epithelial injury in murine
models of GVHD results in translocation of LPS from the intestinal
lumen into the bloodstream (16, 20). Nestel and colleagues (16) have
advanced the concept that immune-activated macrophages are important
effector cells in GVHD. They investigated peritoneal macrophage
activity and TNF- production during GVHD. The data provide evidence
that during GVHD, macrophages are primed as a result of TNF-
produced during the allogeneic reaction, and that endogenous LPS
triggers macrophage production of TNF-, resulting in the symptoms
characteristic of acute GVHD. In a subsequent report, these
investigators have also shown that peritoneal macrophages from mice
with GVHD express elevated mRNA levels of inducible nitric oxide
synthetase and nitric oxides (30).
Similar priming of AM could contribute to acute lung injury, but this
mechanism has not been directly investigated in murine models of marrow
transplantation. Studies of murine transplant models of pneumonitis and
GVHD demonstrated elevated BAL levels of LPS, neutrophils, and TNF-
(20). Injection of LPS caused severe hemorrhagic lung injury only in
mice with GVHD and was associated with marked increases in BAL TNF-.
These data are consistent with our studies that directly demonstrate AM
activation, TNF- production, and increased sensitivity to LPS
challenge both in vitro and in vivo.
Extrapolating these observations to patients with GVHD and noninfectious lung injury is speculative at this time, but the concept of immune-mediated increased susceptibility to LPS and possibly other external factors could help explain the variable association of lung injury with GVHD, the severity of the injury, and the poor response to treatment.
In conclusion, our model of alloreactive Th1-mediated lung injury mimics some features of lung injury encountered in murine models of GVHD. We have established the principle that activated Th1 cells alone can initiate an inflammatory lung injury that is amplified by mononuclear cell recruitment and AM activation and is associated with greatly increased susceptibility to further injury caused by LPS challenge. The cell and cytokine components of immune-mediated lung injury are undoubtedly more complex, but the experimental model we describe offers an opportunity to dissect the cellular and molecular mechanisms involved in this effector pathway.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Joan G. Clark, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N (D3-190), P.O. Box 19024, Seattle, WA 98109-1024. E-mail address:
3 Abbreviations used in this paper: GVHD, graft-vs-host disease; AM, alveolar macrophage; BrdUrd, bromodeoxyuridine; BAL, bronchoalveolar lavage.
4 For clarity of presentation in this manuscript, we will designate the genotype of mice as Ly5a or Ly5b and the specificity of T cell clones according to the gene (Ly5a or Ly5b) that encodes the surface Ag that is recognized.
Received for publication December 22, 1997. Accepted for publication April 9, 1998.
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S. Yang, C. Milla, A. Panoskaltsis-Mortari, S. Hawgood, B. R. Blazar, and I. Y. Haddad Surfactant Protein A Decreases Lung Injury and Mortality after Murine Marrow Transplantation Am. J. Respir. Cell Mol. Biol., September 1, 2002; 27(3): 297 - 305. [Abstract] [Full Text] [PDF]
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S. Yang, V. A. Porter, D. N. Cornfield, C. Milla, A. Panoskaltsis-Mortari, B. R. Blazar, and I. Y. Haddad Effects of oxidant stress on inflammation and survival of iNOS knockout mice after marrow transplantation Am J Physiol Lung Cell Mol Physiol, October 1, 2001; 281(4): L922 - L930. [Abstract] [Full Text] [PDF]
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S. Yang, C. Milla, A. Panoskaltsis-Mortari, D. H. Ingbar, B. R. Blazar, and I. Y. Haddad Human Surfactant Protein A Suppresses T Cell-Dependent Inflammation and Attenuates the Manifestations of Idiopathic Pneumonia Syndrome in Mice Am. J. Respir. Cell Mol. Biol., May 1, 2001; 24(5): 527 - 536. [Abstract] [Full Text]
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K. R. Cooke, G. R. Hill, A. Gerbitz, L. Kobzik, T. R. Martin, J. M. Crawford, J. P. Brewer, and J. L. M. Ferrara Hyporesponsiveness of Donor Cells to Lipopolysaccharide Stimulation Reduces the Severity of Experimental Idiopathic Pneumonia Syndrome: Potential Role for a Gut-Lung Axis of Inflammation J. Immunol., December 1, 2000; 165(11): 6612 - 6619. [Abstract] [Full Text] [PDF]
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J. S. Serody, S. E. Burkett, A. Panoskaltsis-Mortari, J. Ng-Cashin, E. McMahon, G. K. Matsushima, S. A. Lira, D. N. Cook, and B. R. Blazar T-lymphocyte production of macrophage inflammatory protein-1alpha is critical to the recruitment of CD8+ T cells to the liver, lung, and spleen during graft-versus-host disease Blood, November 1, 2000; 96(9): 2973 - 2980. [Abstract] [Full Text] [PDF]
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A. E. Dixon, J. B. Mandac, P. J. Martin, R. C. Hackman, D. K. Madtes, and J. G. Clark Adherence of adoptively transferred alloreactive Th1 cells in lung: partial dependence on LFA-1 and ICAM-1 Am J Physiol Lung Cell Mol Physiol, September 1, 2000; 279(3): L583 - L591. [Abstract] [Full Text] [PDF]
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A. E. Dixon, J. B. Mandac, D. K. Madtes, P. J. Martin, and J. G. Clark Chemokine expression in Th1 cell-induced lung injury: prominence of IFN-gamma -inducible chemokines Am J Physiol Lung Cell Mol Physiol, September 1, 2000; 279(3): L592 - L599. [Abstract] [Full Text] [PDF]
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A. Panoskaltsis-Mortari, D. H. Ingbar, P. Jung, I. Y. Haddad, P. B. Bitterman, O. D. Wangensteen, C. L. Farrell, D. L. Lacey, and B. R. Blazar KGF pretreatment decreases B7 and granzyme B expression and hastens repair in lungs of mice after allogeneic BMT Am J Physiol Lung Cell Mol Physiol, May 1, 2000; 278(5): L988 - L999. [Abstract] [Full Text] [PDF]
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I. Y. Haddad, A. Panoskaltsis-Mortari, D. H. Ingbar, E. R. Resnik, S. Yang, C. L. Farrell, D. L. Lacey, D. N. Cornfield, and B. R. Blazar Interactions of keratinocyte growth factor with a nitrating species after marrow transplantation in mice Am J Physiol Lung Cell Mol Physiol, August 1, 1999; 277(2): L391 - L400. [Abstract] [Full Text] [PDF]
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 A. E. Dixon, J. B. Mandac, P. J. Martin, D. K. Madtes, R. C. Hackman, and J. G. Clark Alloreactive Th1 Cells Localize in Lung and Induce Acute Lung Injury Chest, July 1, 1999; 116 (2009): 36S - 37S. [Full Text]
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