| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Animal Models |
From the Veterinary and Tumor Pathology Section,*
Office of Laboratory Animal Resources, Division of Basic Sciences, and
the Veterinary Pathology Section,
Pathology/Histotechnology Laboratory, SAIC Frederick, National Cancer
Institute at Frederick, Frederick; and the Laboratory of
Metabolism,
Division of Basic Sciences,
National Cancer Institute, Bethesda, Maryland
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
A great many, if not the majority, of genetically engineered mice are constructed using embryonic stem cells derived from a 129/Sv strain injected into C57BL/6 mouse blastocysts. The resulting chimeric animals are then bred back to either the B6 or 129 to fix the new genotype on one or the other background strains with the new designation of B6,129. The natural history of the more standardized C57BL/6 strain has been fairly well chronicled. However, the 129 mouse, although used extensively for genetic studies, has diverged into many sometimes uncharacterized lines and sublines10 with subsequent limited and conflicting information as to endogenous pathology.11 Not surprisingly, the pathology of the relatively new B6,129 mouse, as a co-isogenic strain to 129 and/or C57BL/6, is also not well known.11
In a study of the effect of targeted deletion of the CYP1A2 gene, we discovered high incidences of unusual hyaline gastric, biliary, and respiratory lesions both in one of the progenitor strains,129S4/SvJae, and in the co-isogenic B6,129 mice.11 We identified the hyaline protein and showed distribution of it in normal tissues and in hyalinosis.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Control 129S4/SvJae mice were originally derived from animals bred and maintained in Dr. Heiner Westphal’s laboratory at the National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD. The wild-type and CYP1A2-null B6,129 populations (C57BL6/NCr x 129S4/SvJae, brother x sister matings) were derived from those used in previous CYP1A2 targeted deletion mouse experiments11-14 transferred to National Cancer Institute at Frederick, Frederick, MD, for line maintenance and studies of aging. Groups of 25 to 50 mice of each sex were housed at no more than five per cage; all received NIH 31 diet (PMI, St. Louis, MO) ad libitum and acidified water and were allowed to live out their life spans in compliance with the recommendations of the Guide for the Care and Use of Laboratory Animals of the National Research Council. Mice were sacrificed when conditions suggested progressive deterioration because of aging changes; few mice died spontaneously.
A complete necropsy was performed on all animals with tissues fixed in 10% neutral-buffered formalin, trimmed, and embedded in paraffin. The stomach was inflated with formalin at the time of necropsy, tied off at the pyloric end, and fixed for 5 minutes. It was then opened by cutting along the greater curvature, flattened by sandwiching between filter paper, and fixed further. When adequately flattened and preserved, sequential longitudinal sections were trimmed and embedded according to a specific protocol.15
Tissues from 2- to 4-month-old wild-type B6,129 (ie, CYP1A2 +/+) mice and from our archival motheaten (me/me) mice16 were also collected for histopathological comparisons. Sections were stained with hematoxylin and eosin (H&E). Selected tissues were also stained by the periodic acid-Schiff method, acid fast, Masson’s trichrome, and Dominici and Steiner’s silver.
Immunohistochemistry and Electron Microscopy
Immunohistochemistry was performed on formalin-fixed tissues embedded in paraffin and sectioned at 4 to 6 µm. They were incubated with a rabbit serum raised against two peptide sequences identified on analysis of the gastric lesion protein (see following section) at dilutions of 1:1,000 through 1:64,000 using the Vectastain ABC Rabbit Elite Kit (Vector Laboratories, Inc., Burlingame, CA). Diaminobenzidine was the chromagen with hematoxylin as the counterstain.
Two stomach lesions were chosen for electron microscopy; they were fixed in 2.5% glutaraldehyde, postfixed in osmium tetroxide, and embedded in epoxy resin. Thin sections were cut and stained with uranyl acetate and lead citrate before electron microscopic evaluation.
Gastric Protein Isolation and Identification
Gastric lesions and normal glandular stomach tissues adjacent to the lesions were obtained from 15- to 17-month-old female CYP1A2-null (B6,129) mice. Control stomach tissue was obtained from a 12-month-old wild-type B6,129 female mouse. Tissues were minced with scissors in 5 volumes of ice-cold phosphate-buffered saline (pH 7.5) containing 10 mmol/L ethylenediaminetetraacetic acid, 15 mmol/L MgCl2, 10 mmol/L dithiothreitol, 1 mmol/L phenylmethylsulfonyl fluoride, 10 mg/ml leupeptin, and 10 mg/ml aprotinin. Two volumes of sodium dodecyl sulfate (SDS)-loading buffer17 were added and the suspension boiled for 10 minutes. After brief sonication for 30 seconds, the solution was spun at 10,000 x g for 10 minutes and the supernatant loaded onto 10% SDS-polyacrylamide gels. Protein concentration was determined by use of the BCA protein assay reagent (Pierce Chemical Company, Rockford, IL) using bovine serum albumin as standard.
After separation on SDS-polyacrylamide gels, stomach proteins were transferred to polyvinylidene difluoride membranes (Schleicher & Schuell, Keene, NH) for peptide sequencing and to nitrocellulose membranes (Schleicher & Schuell) for Western blotting. Whole proteins were visualized by gel staining with Coomassie Brilliant Blue R250. Proteins transferred to polyvinylidene difluoride membranes for peptide sequencing were stained with Ponceau S before cutting and subsequent analyses. The antibody was prepared in rabbits using two peptide sequences (Macromolecular Resources, Fort Collins, CO), QYNFDGLNLDWQYPGSRGSPPK and DLHDPKDGYTGENSPLYKSPYD, a part of which was derived from those sequences that were determined by peptide sequencing of the band from the SDS gel and the rest from the published Ym1 sequence (see below). The peptides corresponded to the amino acid residues 130 to 151 and 203 to 234, respectively, based on the first amino acid residue in the precursor Ym1 protein as position 1. Western blots were developed using rabbit anti-peptide antibody and secondary antibody coupled with horseradish peroxidase for enhanced chemiluminescence detection (ECL; Amersham, Arlington Heights, IL).
RNA Analyses
Total RNAs were isolated from various tissues as indicated using
TRIzol reagent (Life Technologies, Inc., Gaithersburg, MD) according to
the manufacturer’s protocol. RNAs were electrophoresed on a 0.22 mol/L
formaldehyde-1% agarose gels, blotted onto a GeneScreen Plus membrane
(NEN Life Science Products, Boston, MA), and hybridized with a Ym2 cDNA
probe that encodes the N-terminal one-fourth of the protein. Because
the 5' region of the Ym2 sequence is not known, a Ym2 cDNA probe of
340 bp was prepared using reverse transcriptase-polymerase chain
reaction (RT-PCR) with stomach RNA and primers designed based on the
published Ym1 sequence,18
assuming that high similarity is
present between entire Ym1 and Ym2 sequences. RT-PCR was also performed
to confirm the identity of mRNAs expressed in various parts of the
stomach. In this case, primer sequences were chosen from the region
where sequences of Ym1 and Ym2 are identical. RT-PCR products were
analyzed with an Applied Biosystems DNA sequencer (model 373A; Applied
Biosystems, Foster City, CA), and MacVector software (Oxford Molecular
Group, Beaverton, OR).
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
50%. The
complete aging pathology of these mice is reported
elsewhere.11
In Table 1
, the
incidence data are based on the pathology of the mice that were
sacrificed because of clinical signs or that died of natural causes.
|
Histologically, an eosinophilic cytoplasmic degenerative change,
ie, hyalinosis, was found in multiple epithelial tissues, but differed
in incidence by mouse strain and sex (Table 1)
. The incidence was
particularly high in the nasal mucosa, trachea, lung, and stomach of
129S4/SvJae and CYP1A2-null mice.
Epithelial cells in the nasal mucosa, trachea, lung, glandular stomach,
gall bladder, bile ducts, and pancreatic ducts showed large cytoplasmic
eosinophilic inclusions, diffuse hyaline cytoplasm, or other
cytoplasmic changes. The respiratory epithelium tended to be most
affected, particularly in the regions of the nasal glands, with
olfactory epithelial involvement occurring primarily near the
olfactory/respiratory transition areas characterized by focal
hyalinosis in the form of eosinophilic inclusions (Figure 1A)
. Affected respiratory epithelial
cells were frequently swollen with peripheral displacement of the
nucleus. In affected olfactory epithelium, the inclusions tended to be
more common and to originate at the basal aspects of lining cells.
Inflammation was usually not associated with epithelial changes. The
occurrence and severity of the lesions varied from mouse to mouse.
Nasal inclusions were also found in 4-month-old wild-type B6,129 mice
and crystal formation seen in 9 to 12% of aged mice of the same
genotype. Crystals were variably needle-like, rectangular, or
square-shaped (Figure 1A)
.
|
Gall bladders were often grossly enlarged with thickened opaque walls
in 129S4/SvJae mice and had eosinophilic cytoplasmic hyaline change.
Extracellular crystals, when present, tended to be large and
rectangular to square in shape. Affected bile ducts had associated
mucoid metaplasia and fibrosis. Masson’s trichrome revealed intense
red staining of eosinophilic gall bladder and bile duct epithelium
(Figure 1B)
. In a few cases, smaller pancreatic ducts had lesions
similar to those in the bile ducts.
Gastric lesions were most common in the cardiac glandular stomach at or
near the limiting ridge (Figure 2)
. These
lesions were most often plaque-like and were frequently multiple, but
localized within the same periesophageal area of the cardia; some were
hemorrhagic. The size of the lesion was apparently a function of age as
the largest lesions were found in the oldest mice. The glandular
epithelium was disorganized focally in the plaque and had loss of
normal differentiation patterns (Figure 1C)
. It was usually also
hyperplastic and contained focal areas of hyalinized epithelial cells
(Figure 1, D and E)
that seemed to arise from chief cells in the
mid-region of the glands. Some epithelial cells contained only a few
intracytoplasmic droplets, whereas other cells were swollen by the
brightly eosinophilic material with a peripherally displaced nucleus.
Extracellular eosinophilic crystals were often focally abundant in the
lumen of the glands, being present in 83% of the CYP1A2-null females
and in only 12.5% of the null males (Figure 1, E and F)
. These
crystals were most often rectangular, as opposed to needle- or
square-shaped; they were metachromatic with Dominici stain (Figure 1F)
as were the hyaline granules within epithelial cells.
|
. Chronic to chronic-active inflammatory foci in the wall of the
glandular stomach, often with eosinophils or a mixed inflammatory cell
response, were often associated with the plaques of the CYP1A2-null
mice (41 to 96%) but were less frequently found in 129S4/SvJae gastric
lesions (30%). Steiner’s staining usually revealed no helical
organisms in the lumen or glands. Forestomach squamous hyperplasia was
observed in some mice and eosinophilic inclusions were sometimes
present in the stratum spinosum.
Ultrastructure of two gastric lesions revealed abundant pale granular
material within dilated rough endoplasmic reticulum in what appeared to
be chief cells; in addition, these cells often contained some secretory
granules (Figure 3)
. Some cells had one
large dilated cisterna whereas in others multiple cisternae were
affected. We found no evidence of obvious parietal cell origin.
|
Proteins obtained from the lesion, normal part of the glandular
stomach adjacent to the lesion, and normal glandular stomach were
subjected to SDS-polyacrylamide gel electrophoresis, followed by
protein staining. A protein band of 45 kd was detected in only the
lesion sample, but not the others (Figure 4)
. After proteins were transferred to a
membrane and were visualized, the corresponding band was excised from
the gel and subjected to peptide sequencing. Two peptide sequences were
obtained that matched those of secretory protein Ym118
when subjected to a GenBank search. This protein belongs to a chitinase
family, and is also known as a chitinase-related protein (GenBank
U56900) or T lymphocyte-derived eosinophil chemotactic factor
(ECF-L).19
Antibody was prepared using a part of these
peptide sequences with the extension of several amino acid residues
based on the published Ym1 sequence,18,19
which exhibited
good antigenicity by computer analyses.
|
55 kd, in addition to the 45-kd
band (Figure 5A)
. This 55-kd protein was
detected in the normal part of the glandular stomach adjacent to the
lesion as well as in the normal glandular stomach, whereas the 45-kd
protein was seen only in the lesion and in normal forestomach. The
gastric limiting ridge exhibited both 45- and 55-kd bands. Expression
level of the 45-kd protein in the lesion varied depending on samples,
from as low as 20-fold to as high as 200-fold greater than the level of
the 55-kd protein present in the adjacent normal part of the glandular
stomach or normal glandular stomach. This is based on the fact that the
amount of total lesion protein loaded on a gel was reduced such that
the intensity of the 55-kd band and the lesion 45-kd band were
equivalent. The antibody also reacted to a reduced extent, with a
protein of 50 kd expressed in the lung and spleen, and two bands of
42 kd in the liver (Figure 5B)
.
|
Northern blotting analyses were also performed to examine the level of
Ym2 mRNA expression (Figure 6, A and B)
.
Ym2 mRNA was 1.6 kb, and the expression level in the stomach lesion
was at least 20 times higher than the normal part of the glandular
stomach adjacent to the lesion. Northern blotting analyses also
revealed that a Ym2 cDNA probe cross-hybridized with mRNA expressed in
the lung and spleen, which is slightly larger than the stomach-specific
Ym2 mRNA (Figure 6B)
.
|
Using the rabbit polyclonal antibody raised against the two
oligopeptides whose sequences are derived from Ym1, immunohistochemical
evaluation of tissues from normal young mice of both the 129S4/SvJae
and B6,129 lines revealed immunoreactivity in olfactory and respiratory
nasal epithelium (Figure 7A)
, most
pulmonary alveolar macrophages (Figure 7B)
, and some alveolar type II
cells, bone marrow myeloid cells (Figure 7C)
, and the squamous
epithelium of the oral cavity, esophagus, and limiting ridge of the
stomach (Figure 7D)
. In wild-type B6,129 mice, some chief and parietal
cells in the lower portion of the gastric glands in the fundus had
either diffuse cytoplasmic reactivity or peripheral cytoplasmic
granular reactivity (Figure 7E)
. The staining pattern varied from
granular cytoplasmic in alveolar type II cells, diffuse cytoplasmic in
squamous epithelium and bone marrow, and vacuolated-diffuse cytoplasmic
in normal nasal epithelium.
|
,
normal, hyperplastic, or inflammatory gall bladder and bile ducts
(Figure 7G)
, the immunostaining pattern was often diffuse and
cytoplasmic but focal or granular patterns were also seen. The
pulmonary macrophages of 129S4/SvJae (Figure 7H)
and motheaten mice
(Figure 7I)
with macrophage pneumonias displayed diffuse cytoplasmic
staining. Gastric plaques in both B6,129 and 129S4/SvJae animals
demonstrated a diffuse cytoplasmic immunostaining of inclusions and
hyperplastic cells; extracellular crystals were also immunoreactive.
CYP1A2-null mice sometimes showed focal to diffuse reactivity
throughout epithelium distant from the gastric plaques themselves.
Within the gastric lesions, immunostaining was usually focal and not
all cells with inclusions were positive. |
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
In contrast, hyaline lesions of the nasal cavity and respiratory tract identical to those described in our study, have been found in other conventional mice.11,22-26 Hyalinosis in gall bladders and in bile and pancreatic ducts has also been reported previously in these same and several other mouse strains or stocks.11,13,14,27-29 The characteristic pulmonary lesions containing macrophages with eosinophilic crystal formation seen in our 129S4/SvJae population, furthermore, resemble those reported in the motheaten mouse16,22,30,31 and are sometimes associated with lung tumors32,33 as well as with macrophage pneumonias in a number of strains.22,27 In motheaten mice, the pulmonary macrophage lesion is associated with a deficiency of SHP-1, a protein tyrosine phosphatase.34
We have identified that extracellular and intracellular eosinophilic
crystals in the gastric lesion are composed of secretory protein
Ym2. Ym2 is highly related to Ym1 (GenBank M94584),18
the
latter of which is also called eosinophil chemotactic factor (ECF-L,
GenBank D87757),19
a chitinase-related protein. Ym1 and
Ym2 share 95% identity but show tissue-specific expression; whereas
Ym1 expression is high in lung and spleen and barely detectable
in stomach, Ym2 expression is high in stomach and nondetectable
in lung and spleen.18
Ym2 is also detectable in the thymus
to a lesser extent than the stomach. Together with these results, our
findings suggest that Ym2 may be a stomach-specific eosinophil
chemotactic cytokine.
The mature form of Ym1/ECF-L is a processed product of the precursor that has a signal peptide at the N-terminus.19 On the analogy of Ym1, it is likely that the 55-kd protein is a precursor and the 45-kd protein is a mature form of Ym2. Our Western blotting results demonstrate that the 55-kd precursor protein is predominantly produced in the glandular stomach whereas the 45-kd protein is abundant in the forestomach. This may suggest that the precursor protein is mainly produced in the glandular stomach, which moves to the forestomach as the protein is processed. Because the junction (limiting ridge) between the glandular stomach and the forestomach contains both 55- and 45-kd proteins, the protein processing may take place at or near the limiting ridge. The mechanism for this processing relative to the histological structure of the stomach remains unclear.
Our Western blotting results demonstrated that the level of Ym2 protein massively increased in the gastric lesion. Especially of interest is that the majority of increased Ym2 protein is a mature form. This explains why the 45-kd protein was initially detected only in the lesion, but not in the other stomach samples on SDS-polyacrylamide gels. In contrast, normal stomach has both the precursor and the mature form at comparable levels. Increased expression of Ym2 mRNA was also observed in the lesion, indicating that the increased level of Ym2 protein expression is mainly because of increased level of Ym2 mRNA. The mechanism for this increase in mRNA is not known. Increased levels of Ym2 precursor may facilitate the processing machinery in massively accumulating mature form of Ym2, which results in crystallization and formation of the lesion.
Because the antibody used in the current study was raised against
peptides, whose sequences are derived from the Ym1 sequence and a high
degree of sequence similarity is present between Ym1 and Ym2, and
possibly other members of chitinase family,18,35
we are
most likely showing a certain amount of cross-reactivity for murine
chitinase-like protein products. In fact, Western blots of lung and
spleen exhibited a protein band of 50 kd and additional protein
bands of 42 kd were identified in liver. Because Ym1 is purported to
be expressed in lung and spleen rather than in stomach18
it is reasonable to assume that the 50-kd protein may be Ym1. This is
further supported by a recent study22
in which Ym1 was
isolated from endogenously formed eosinophilic crystals in the lungs of
motheaten
(mev/mev) mice.
Another member of the chitinase gene family, Ym3, has been described
that shares 95% identity with Ym1 and Ym2.18
Although
the total length and sequence is not known for Ym3, the degree of
homology would not preclude detection of this isoform as well. The
42-kd proteins present in liver could therefore be Ym3 although Ym3
expression was not detected in the liver.18
The 42-kd
proteins consist of two bands, the second band being smaller in size
and fainter than the main band, suggesting that the second band may be
a degradation product. Alternatively, the upper band is a precursor and
the second band is a mature form of the protein, given that the protein
is Ym3, and this protein also goes through the same processing as Ym1
and Ym2. The identity of the immunoreactive proteins found in the
olfactory and nasal cavity, bone marrow, oral cavity, esophagus, bile
duct, and gall bladder could be Ym1, 2, 3, or as yet unidentified
members of the chitinase-like family.
The data presented in this experiment suggest that sex and strain genetics can highly influence the prevalence of gastric lesions and that CYP1A2 seems to exert a sex-specific moderating effect on the expression/production of particular protein secretions by some means. Exactly which hormone or hormones may be involved is not clear since ancillary investigations of other gastric products and modifiers have not yet been performed. However, the markedly higher female incidence of these hyaline lesions in both the control 129S4/SvJae and the wild-type and 1A2-null B6,129 animals implicates a sex-specific signal and some form of estrogen is, at least on the surface, a likely candidate. The highest frequencies of hyalinosis in the background 129S4/SvJae strain occurred in the lung and in the respiratory epithelium of the nasal cavity; the primary cause of death in this population was, in fact, macrophage pneumonia.11 Although the incidence in an equivalently aged population of naïve C57BL/6 was not examined in this study, the B6,129 descendents of these strains demonstrate a shift of hyaline lesions toward involvement of the respiratory and olfactory epithelia of the nasal mucosa and away from lung. C57BL/6 mice seem to be refractory to the formation of spontaneous lung tumors,32,36 as well as to the acidophilic macrophage pneumonia seen in this and other aging studies.33,37 Despite genetic make-up, however, female mice are always more frequently affected. Only in the CYP1A2-null groups do the male incidences approach those of the females, again suggesting some hormonal influence kept in check by CYP1A2.
The positive immunoreactivity of the Ym1/2 antibodies with macrophages in archival motheaten mouse lung implies that at least part of the etiology of this condition is based in normal physiology gone awry. There are some similarities of the hyalinosis syndrome in our mice to autoimmune disorders. The motheaten syndrome is an immunodeficient and autoimmune condition comprising abnormal neutrophil accumulations in tissues and abnormal macrophage physiology that includes the formation of eosinophilic crystals.16,30,38 Being a spontaneous mutant in the B6 strain implicates a possible susceptibility of the respiratory tract in this strain to macrophage-mediated insult. Noteworthy is the chronic ulcerative dermatitis frequently encountered in C57BL/6 and C57BL/10 populations that is characterized by a mixed cell infiltrate including macrophages and neutrophils.39 Many, if not most, autoimmune diseases are more prevalent and/or more severe in females40,41 and control of autoimmune reactions might be a P450 homeostatic function. Chitinases can act on the acetylglucosamine moieties found not only in exogenous chitins of fungi, bacteria, plants, parasites, and insects, but possibly on similar glycosaminoglycans formed by endogenous polysaccharides in the extracellular matrices as well; patients suffering from rheumatoid arthritis and Gaucher’s disease have been shown to have elevated levels of chitinase-like proteins.22
The surprising increase in the incidence of female gastric lesions on deletion of CYP1A2 may be the clearest evidence of involvement of this cytochrome subfamily in normal physiological events. Even though the function of CYP1A2 has been fairly well determined within the context of its exogenous substrates, eg, aromatic and heterocyclic amines,5 its endogenous substrates have not been fully identified, possibly because high induction may not be necessary in homeostatic reactions. This would be especially true if CYP1A2 served as a watchdog of metabolic activities directly mediated by other substances, such as hormones and cytokines. Although CYP1A2 expression has been detected only in liver,42 the absence of expression in other organs does not necessarily mean lack of activity, either directly within tissues and/or via feedback from extrahepatic sites.
In higher vertebrates, chitinases are believed to act as sentinels against parasites as well as having some digestive capabilities for chitin moieties in plant and insect ingesta.43 ECF-L has been shown to cause extravasation of eosinophils and recruitment of T cells in response to parasitic infections, especially invasive helminth exposures.19 Targeted mutation of CYP1A2 apparently allows for the overproduction of Ym2 protein, which may be the gastric-specific isoform of ECF-L that accumulates in the lumens of the glands of the gastric cardia and eventually leads to the characteristic hyperplastic lesions. The incidence in CYP1A2-null females is nearly threefold greater than in null males, in contrast to the low but slightly elevated male incidences in WT animals. This argues that CYP1A2 exerts some regulatory effect, but that it is possibly indirect and exerting the effect through a hormone with sexual dimorphism, if not sex-specificity. Thus, a candidate would logically be estrogen. The CYP1A1 gene has been found to be regulated by glucocorticoids via the XRE-Ahr-Arnt binding complex.5
Another candidate, maybe more pertinent in the case of the gastric lesions induced in CYP1A2-null mice, is bombesin or, specifically gastrin-releasing peptide, which initiates the release of gastrin and other substances in the glandular stomach, duodenum, and pancreatic islets.44,45 Both bombesin and gastrin-releasing peptide have been shown to play roles in lung morphogenesis46,47 and in maintenance of mucosal immunity in both the gastrointestinal and respiratory tracts.48,49 Two other possibilities are growth hormone (somatotropin) and insulin, possibly mediated by gastrin-releasing peptide. All operate within liver feedback systems and can be tissue-specific; in fact, glucose levels have been shown to regulate the effect of both bombesin and gastrin-releasing peptide.45 In addition, another cytochrome, CYP2E1 has been shown to be regulated by growth hormone.50
The data from the lungs and upper respiratory tract seems to parallel those in the stomach, and probably for the same reasons. Ingestion and inhalation are the two most frequent methods of exposure to any parasite or toxin and, therefore, it is possible that similar systems be operating along the same routes. It is also conceivable that for exogenous substrates similar to those found endogenously, a moderating surveillance mechanism be in place to control an overexuberant response that might prove harmful to the body. This study suggests a role for CYP1A2 moderating a complex hormonal control of YM1/2 as surveillance proteins in the mouse respiratory and gastrointestinal tracts.
|
Acknowledgements |
|---|
|
Footnotes |
|---|
Supported in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract NO1-CO-5600 to SAIC Frederick.
G. K.’s current address: Daiichi Pharmaceutical Co., Tokyo 134-0081 Japan.
The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.
Accepted for publication September 13, 2000.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
disrupts the normal program of cellular differentiation in the gastric mucosa of transgenic mice. Development 1995, 121:149-161[Abstract]
This article has been cited by other articles:
 |
|
 |
|
  M. A. Mall, J. R. Harkema, J. B. Trojanek, D. Treis, A. Livraghi, S. Schubert, Z. Zhou, S. M. Kreda, S. L. Tilley, E. J. Hudson, et al. Development of Chronic Bronchitis and Emphysema in {beta}-Epithelial Na+ Channel-Overexpressing Mice Am. J. Respir. Crit. Care Med., April 1, 2008; 177(7): 730 - 742. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Doi, Y. Kotani, H. Kokoshima, T. Kanno, Y. Wako, and M. Tsuchitani Eosinophilic Substance is "Not Amyloid" in the Mouse Nasal Septum Vet. Pathol., November 1, 2007; 44(6): 796 - 802. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. G. Fox, A. B. Rogers, M. T. Whary, Z. Ge, M. Ohtani, E. K. Jones, and T. C. Wang Accelerated Progression of Gastritis to Dysplasia in the Pyloric Antrum of TFF2 / C57BL6 x Sv129 Helicobacter pylori-Infected Mice Am. J. Pathol., November 1, 2007; 171(5): 1520 - 1528. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. P. Bussink, D. Speijer, J. M. F. G. Aerts, and R. G. Boot Evolution of Mammalian Chitinase(-Like) Members of Family 18 Glycosyl Hydrolases Genetics, October 1, 2007; 177(2): 959 - 970. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. D. Milner, J. M. Ward, A. Keane-Myers, and W. E. Paul Lymphopenic mice reconstituted with limited repertoire T cells develop severe, multiorgan, Th2-associated inflammatory disease PNAS, January 9, 2007; 104(2): 576 - 581. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. L. Mora, E. Torres-Gonzalez, M. Rojas, C. Corredor, J. Ritzenthaler, J. Xu, J. Roman, K. Brigham, and A. Stecenko Activation of Alveolar Macrophages via the Alternative Pathway in Herpesvirus-Induced Lung Fibrosis Am. J. Respir. Cell Mol. Biol., October 1, 2006; 35(4): 466 - 473. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Hoenerhoff, M. F. Starost, and J. M. Ward Eosinophilic Crystalline Pneumonia as a Major Cause of Death in 129S4/SvJae Mice. Vet. Pathol., September 1, 2006; 43(5): 682 - 688. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Marchesi, S. Minucci, P. G. Pelicci, A. Gobbi, and E. Scanziani Immunohistochemical Detection of Ym1/Ym2 Chitinase-like Lectins Associated with Hyalinosis and Polypoid Adenomas of the Transitional Epithelium in a Mouse with Acute Myeloid Leukemia. Vet. Pathol., September 1, 2006; 43(5): 773 - 776. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. R. Harkema, S. A. Carey, and J. G. Wagner The Nose Revisited: A Brief Review of the Comparative Structure, Function, and Toxicologic Pathology of the Nasal Epithelium Toxicol Pathol, April 1, 2006; 34(3): 252 - 269. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. B. Rogers, N. S. Taylor, M. T. Whary, E. D. Stefanich, T. C. Wang, and J. G. Fox Helicobacter pylori but not High Salt Induces Gastric Intraepithelial Neoplasia in B6129 Mice Cancer Res., December 1, 2005; 65(23): 10709 - 10715. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Yang, J. Gao, M. Adamian, X.-H. Wen, B. Pawlyk, L. Zhang, M. J. Sanderson, J. Zuo, C. L. Makino, and T. Li The Ciliary Rootlet Maintains Long-Term Stability of Sensory Cilia Mol. Cell. Biol., May 15, 2005; 25(10): 4129 - 4137. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Brenner, D. Levanon, V. Negreanu, O. Golubkov, O. Fainaru, E. Woolf, and Y. Groner Loss of Runx3 function in leukocytes is associated with spontaneously developed colitis and gastric mucosal hyperplasia PNAS, November 9, 2004; 101(45): 16016 - 16021. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Howroyd, C. Swanson, C. Dunn, R. C. Cattley, and J. C. Corton Decreased Longevity and Enhancement of Age-Dependent Lesions in Mice Lacking the Nuclear Receptor Peroxisome Proliferator-Activated Receptor {alpha} (PPAR{alpha}) Toxicol Pathol, August 1, 2004; 32(5): 591 - 599. [Abstract] [PDF]
|
|
|
|
 |
|
 J. G. Fox, A. B. Rogers, M. T. Whary, Z. Ge, N. S. Taylor, S. Xu, B. H. Horwitz, and S. E. Erdman Gastroenteritis in NF-{kappa}B-Deficient Mice Is Produced with Wild-Type Camplyobacter jejuni but Not with C. jejuni Lacking Cytolethal Distending Toxin despite Persistent Colonization with Both Strains Infect. Immun., February 1, 2004; 72(2): 1116 - 1125. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. G. Sandler, M. M. Mentink-Kane, A. W. Cheever, and T. A. Wynn Global Gene Expression Profiles During Acute Pathogen-Induced Pulmonary Inflammation Reveal Divergent Roles for Th1 and Th2 Responses in Tissue Repair J. Immunol., October 1, 2003; 171(7): 3655 - 3667. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. S. Welch, L. Escoubet-Lozach, D. B. Sykes, K. Liddiard, D. R. Greaves, and C. K. Glass TH2 Cytokines and Allergic Challenge Induce Ym1 Expression in Macrophages by a STAT6-dependent Mechanism J. Biol. Chem., November 1, 2002; |
