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Biomedical subjects

B H Koller

Publications and source records attributed to B H Koller.

At least 19 recordsLinked to original sources
PubMed2006

Ocular inflammatory responses in the EP2 and EP4 receptor knockout mice.

PURPOSE: To examine the role of EP2 and EP4 receptors in murine ocular inflammation. METHODS: Prostaglandin EP2 and EP4 receptor knockout and wild-type mice were treated topically with prostaglandin E2, SDF-1, and RANTES and lipopolysaccharide by intravitreal injection. Paracentesis was performed by puncturing the cornea. The increase in the level of aqueous humor protein and the number of leukocytes were measured and the vascular leakage of protein was visualized using fluorescein angiography. RESULTS: In the EP2 receptor knockout mice, there was significant inhibition of the disruption of the blood-aqueous barrier caused by lipopolysaccharides, paracentesis, prostaglandin E2, SDF-1, and RANTES. Reductions in the disruption in the blood-aqueous barrier and leukocyte infiltration after lipopolysaccharide injection and paracentesis were significant, but there was no increase in the aqueous humor protein level after prostaglandin E2 treatment in EP4 receptor knockout mice. CONCLUSIONS: The results of the present experiments suggest that EP2 and EP4 receptors partly mediate the disruption of the blood-aqueous barrier and leukocyte infiltration induced by prostaglandin E2, SDF-1, RANTES, and lipopolysaccharides.

Animals↗
PubMed2001

Deficiency of 5-lipoxygenase accelerates renal allograft rejection in mice.

Acute renal allograft rejection is associated with alterations in renal arachidonic acid metabolism, including enhanced synthesis of leukotrienes (LTs). LTs, the products of the 5-lipoxygenase (5-LO) pathway, are potent lipid mediators with a broad range of biologic activities. Previous studies, using pharmacological agents to inhibit LT synthesis or activity, have implicated these eicosanoids in transplant rejection. To further investigate the role of LTs in acute graft rejection, we transplanted kidneys from CByD2F1 mice into fully allogeneic 129 mice that carry a targeted mutation in the 5lo gene. Unexpectedly, allograft rejection was significantly accelerated in 5-LO-deficient mice compared with wild-type animals. Despite the marked reduction in graft survival, the 5lo mutation had no effect on the hemodynamics or morphology of the allografts. Although LTB4 levels were reduced, renal thromboxane B2 production and cytokine expression were not altered in 5-LO-deficient allograft recipients. These findings suggest that, along with their proinflammatory actions, metabolites of 5-LO can act to enhance allograft survival.

Animals↗
PubMed2001

Impact of ionizing radiation and genetic background on mammary tumorigenesis in p53-deficient mice.

Loss of p53 function is known to compromise cell cycle regulation, inductionof apoptosis, and DNA damage repair and can facilitate neoplastic transformation of cells. Mutations in the p53 gene are identified frequently in breast carcinomas. Li-Fraumeni patients inheriting a mutant p53 allele have an increased risk for developing tumors including breast cancer. Although mouse lines carrying mutations in the p53 gene have been generated, they die primarily of lymphoma and thus to date provide a limited model for the study of this disease and the role of p53 in nonfamilial breast cancer. An increasing body of literature suggests that the incidence of various tumors is determined largely by the genetic background on which mutations are studied. In addition, population studies and studies in animals suggest that environmental factors, together with genetic factors, determine overall risk for development of specific types of tumors. We therefore examined the impact of genetic background together with exposure to ionizing radiation on the development of tumors, particularly mammary tumors, in p53-deficient animals. We report here that modifier alleles present in the BALB/c strain increase the incidence of hemangiosarcomas [15 of 53 (28.3%); P = 0.0007] in p53(-/-) mice above rates reported previously in p53(-/-) mice on a mixed background as compared to the incidence observed in DBA/p53(-/-) mice. However, no increase in the frequency of mammary tumors is seen in these mice or in p53(-/-) DBA/2 animals, nor was an increase in mammary tumors observed in the DBA/2 p53(+/-) mice, even after exposure to 5 Gy of whole-body ionizing radiation. In contrast, a significant increase in the incidence of mammary tumors was observed in similarly treated BALB/c p53(+/-) mice (37.3% versus 6.8%; P = 0.0007). This was accompanied by a comparable decrease in the incidence of lymphomas. These results show that environmental agents together with genetic factors can increase the frequency and decrease the latency of mammary tumors, leading to an incidence similar to that observed in Li-Fraumeni syndrome. Furthermore, it suggests that the risk of development of a particular type of tumor by individuals deficient in p53 after exposure to damaging agents can be influenced by modifier alleles.

Alleles↗
PubMed2001

BRCA1 is a selective co-activator of 14-3-3 sigma gene transcription in mouse embryonic stem cells.

BRCA1 gene is a tumor suppressor for breast and ovarian cancers with the putative role in DNA repair and transcription. To characterize the role of BRCA1 in transcriptional regulation, we analyzed gene expression profiles of mouse embryonic stem cells deficient in BRCA1 using microarray technology. We found that loss of BRCA1 correlated with decreased expression of several groups of genes including stress response genes, cytoskeleton genes, and genes involved in protein synthesis and degradation. Previous study showed that BRCA1 is a transcriptional co-activator of p53 protein; however the majority of p53 target genes remained at the same expression levels in BRCA1 knockout cells as in the wild type cells. The only p53 target gene down-regulated with the loss of BRCA1 was 14-3-3 sigma, a major G(2)/M checkpoint control gene. Similar to cells with decreased 14-3-3 sigma activity, BRCA1-deficient cells were unable to sustain G(2)/M growth arrest after exposure to ionizing radiation. We find that BRCA1 induction of 14-3-3 sigma requires the presence of wild type p53 and can be regulated by a minimal p53 response element.

14-3-3 Proteins↗
PubMed2001

The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity.

The pregnane X receptor (PXR) is the molecular target for catatoxic steroids such as pregnenolone 16alpha-carbonitrile (PCN), which induce cytochrome P450 3A (CYP3A) expression and protect the body from harmful chemicals. In this study, we demonstrate that PXR is activated by the toxic bile acid lithocholic acid (LCA) and its 3-keto metabolite. Furthermore, we show that PXR regulates the expression of genes involved in the biosynthesis, transport, and metabolism of bile acids including cholesterol 7alpha-hydroxylase (Cyp7a1) and the Na(+)-independent organic anion transporter 2 (Oatp2). Finally, we demonstrate that activation of PXR protects against severe liver damage induced by LCA. Based on these data, we propose that PXR serves as a physiological sensor of LCA, and coordinately regulates gene expression to reduce the concentrations of this toxic bile acid. These findings suggest that PXR agonists may prove useful in the treatment of human cholestatic liver disease.

Animals↗
PubMed2001

Failure of ductus arteriosus closure and remodeling in neonatal mice deficient in cyclooxygenase-1 and cyclooxygenase-2.

The transition to pulmonary respiration following birth requires rapid alterations in the structure of the mammalian cardiovascular system. One dramatic change that occurs is the closure and remodeling of the ductus arteriosus (DA), an arterial connection in the fetus that directs blood flow away from the pulmonary circulation. A role for prostaglandins in regulating the closure of this vessel has been supported by pharmacological and genetic studies. The production of prostaglandins is dependent on two cyclooxygenases (COX-1 and COX-2), which are encoded by separate genes. We report here that the absence of either or both COX isoforms in mice does not result in premature closure of the DA in utero. However, 35% of COX-2(-/-) mice die with a patent DA within 48 h of birth. In contrast, the absence of only the COX-1 isoform does not affect closure of the DA. The mortality (35%) and patent DA incidence due to absence of COX-2 is, however, significantly increased (79%) when one copy of the gene encoding COX-1 is also inactivated. Furthermore, 100% of the mice deficient in both isoforms die with a patent DA within 12 h of birth, indicating that in COX-2-deficient mice, the contribution of COX-1 to DA closure is gene dosage-dependent. Together, these data establish roles for COX-1, and especially for COX-2, in the transition of the cardiopulmonary circulation at birth.

Animals↗
PubMed2001

Altered cytokine production in mice lacking P2X(7) receptors.

The P2X(7) receptor (P2X(7)R) is an ATP-gated ion channel expressed by monocytes and macrophages. To directly address the role of this receptor in interleukin (IL)-1 beta post-translational processing, we have generated a P2X(7)R-deficient mouse line. P2X(7)R(-/-) macrophages respond to lipopolysaccharide and produce levels of cyclooxygenase-2 and pro-IL-1 beta comparable with those generated by wild-type cells. In response to ATP, however, pro-IL-1 beta produced by the P2X(7)R(-/-) cells is not externalized or activated by caspase-1. Nigericin, an alternate secretion stimulus, promotes release of 17-kDa IL-1 beta from P2X(7)R(-/-) macrophages. In response to in vivo lipopolysaccharide injection, both wild-type and P2X(7)R(-/-) animals display increases in peritoneal lavage IL-6 levels but no detectable IL-1. Subsequent ATP injection to wild-type animals promotes an increase in IL-1, which in turn leads to additional IL-6 production; similar increases did not occur in ATP-treated, LPS-primed P2X(7)R(-/-) animals. Absence of the P2X(7)R thus leads to an inability of peritoneal macrophages to release IL-1 in response to ATP. As a result of the IL-1 deficiency, in vivo cytokine signaling cascades are impaired in P2X(7)R-deficient animals. Together these results demonstrate that P2X(7)R activation can provide a signal that leads to maturation and release of IL-1 beta and initiation of a cytokine cascade.

Adenosine Triphosphate↗
PubMed2001

Ultrastructure of the inner ear of NKCC1-deficient mice.

The transduction of the auditory signal is dependent on the flow of ions within the inner ear. We have generated mice deficient in NKCC1, an ion cotransporter that is thought to be involved in the secretion of K+ by the strial marginal cells. Inner ear histology revealed partial to almost total absence of the scala media and collapse of Reissner's membrane. Ultrastructural analysis showed that Reissner's membrane consists of 3-4 cell layers instead of the usual two, and a substance of unknown composition is present between Reissner's membrane and underlying structures. Within the tunnel of Corti, hair cells and supporting cells were difficult to identify. The location of the tectorial membrane was altered, and a precipitate was observed surrounding it. Severe structural defects were noted in the interdental cells and Boettcher cells, and mild defects were observed in the stria vascularis and in type II and type IV fibrocytes. The finding that major defects occur predominantly in cells that are not known to express NKCC1 suggests that loss of NKCC1 results in functional defects in cells expressing NKCC1 and a morphological effect on cell populations downstream in the proposed K+ recycling pathway.

Animals↗
PubMed2001

Alterations in airway ion transport in NKCC1-deficient mice.

Airways of Na(+)-K(+)-2Cl(-) (NKCC1)-deficient mice (-/-) were studied in Ussing chambers to determine the role of the basolateral NKCC1 in transepithelial anion secretion. The basal short-circuit current (I(sc)) of tracheae and bronchi from adult mice did not differ between NKCC1-/- and normal mice, whereas NKCC1-/- tracheae from neonatal mice exhibited a significantly reduced basal I(sc). In normal mouse tracheae, sensitivity to the NKCC1 inhibitor bumetanide correlated inversely with the age of the mouse. In contrast, tracheae from NKCC1-/- mice at all ages were insensitive to bumetanide. The anion secretory response to forskolin did not differ between normal and NKCC1-/- tissues. However, when larger anion secretory responses were induced with UTP, airways from the NKCC1-/- mice exhibited an attenuated response. Ion substitution and drug treatment protocols suggested that HCO secretion compensated for reduced Cl(-) secretion in NKCC1-/- airway epithelia. The absence of spontaneous airway disease or pathology in airways from the NKCC1-/- mice suggests that the NKCC1 mutant mice are able to compensate adequately for absence of the NKCC1 protein.

Aging↗
PubMed2001

Role of EP(2) and EP(3) PGE(2) receptors in control of murine renal hemodynamics.

The kidney plays a central role in long-term regulation of arterial blood pressure and salt and water homeostasis. This is achieved in part by the local actions of paracrine and autacoid mediators such as the arachidonic acid-prostanoid system. The present study tested the role of specific PGE(2) E-prostanoid (EP) receptors in the regulation of renal hemodynamics and vascular reactivity to PGE(2). Specifically, we determined the extent to which the EP(2) and EP(3) receptor subtypes mediate the actions of PGE(2) on renal vascular tone. Renal blood flow (RBF) was measured by ultrasonic flowmetry, whereas vasoactive agents were injected directly into the renal artery of male mice. Studies were performed on two independent mouse lines lacking either EP(2) or EP(3) (-/-) receptors and the results were compared with wild-type controls (+/+). Our results do not support a unique role of the EP(2) receptor in regulating overall renal hemodynamics. Baseline renal hemodynamics in EP(2)-/- mice [RBF EP(2)-/-: 5.3 +/- 0.8 ml. min(-1). 100 g kidney wt(-1); renal vascular resistance (RVR) 19.7 +/- 3.6 mmHg. ml(-1). min. g kidney wt] did not differ statistically from control mice (RBF +/+: 4.0 +/- 0.5 ml. min(-1). 100 g kidney wt(-1); RVR +/+: 25.4 +/- 4.9 mmHg. ml(-1). min. 100 g kidney wt(-1)). This was also the case for the peak RBF increase after local PGE(2) (500 ng) injection into the renal artery (EP(2)-/-: 116 +/- 4 vs. +/+: 112 +/- 2% baseline RBF). In contrast, we found that the absence of EP(3) receptors in EP(3)-/- mice caused a significant increase (43%) in basal RBF (7.9 +/- 0.8 ml. min(-1). g kidney wt(-1), P < 0.05 vs. +/+) and a significant decrease (41%) in resting RVR (11.6 +/- 1.4 mmHg. ml(-1). min. g kidney wt(-1), P < 0.05 vs. +/+). Local administration of 500 ng of PGE(2) into the renal artery caused more pronounced renal vasodilation in EP(3)-/- mice (128 +/- 2% of basal RBF, P < 0.05 vs. +/+). We conclude that EP(3 )receptors mediate vasoconstriction in the kidney of male mice and its actions are tonically active in the basal state. Furthermore, EP(3) receptors are capable of buffering PGE(2)-mediated renal vasodilation.

Animals↗
PubMed2001

Liquid and ion transport by fetal airway and lung epithelia of mice deficient in sodium-potassium-2-chloride transporter.

Chloride (Cl(-)) movement across fetal lung epithelia is thought to be mediated by the sodium-potassium-2-Cl(-) cotransporter NKCC1. We studied the role of NKCC1 in Cl(-) and liquid secretion in late-gestation NKCC-null (-/-) and littermate control fetal mouse lung. NKCC -/- mice had decreased lung water compared with littermate controls (wet/dry: control, 8.01 +/- 0.09; NKCC -/-, 7.06 +/- 0.14). Liquid secretion by 17-d NKCC -/- distal lung explants was similar to control explants. Bumetanide inhibited basal liquid secretion in control but not NKCC -/- explants (expansion over 48 h: control, 35 +/- 4%; NKCC -/- 46 +/- 7%). Treatment with 4,4'-diisothiocyanto-stilbene-2,2'-disulfonic acid (DIDS) decreased liquid secretion in both control and NKCC -/- explants. Basal transepithelial potential difference (PD) of control tracheal explants was higher than that of NKCC -/- (control, -13.7 +/- 0.5 mV; NKCC -/-, -11.6 +/- 0.6 mV). Amiloride (10(-)(4) M) inhibited basal PD to the same extent in control and NKCC -/- mice. Terbutaline-stimulated hyperpolarization was less in NKCC -/- than in control tracheas (DeltaPD: control, -10.8 +/- 1.33 mV; NKCC -/-, -6.1 +/- 0.7 mV) and was inhibited by DIDS and acetazolamide in NKCC -/- but not wild-type explants. We conclude that NKCC is rate-limiting for transcellular Cl(-) transport, and that alternative anion transport mechanisms can sustain liquid production at near-normal levels in the fetal NKCC -/- mouse lung.

Animals↗
PubMed2001

Activation of the murine EP3 receptor for PGE2 inhibits cAMP production and promotes platelet aggregation.

The importance of arachidonic acid metabolites (termed eicosanoids), particularly those derived from the COX-1 and COX-2 pathways (termed prostanoids), in platelet homeostasis has long been recognized. Thromboxane is a potent agonist, whereas prostacyclin is an inhibitor of platelet aggregation. In contrast, the effect of prostaglandin E2 (PGE2) on platelet aggregation varies significantly depending on its concentration. Low concentrations of PGE2 enhance platelet aggregation, whereas high PGE2 levels inhibit aggregation. The mechanism for this dual action of PGE2 is not clear. This study shows that among the four PGE2 receptors (EP1-EP4), activation of EP3 is sufficient to mediate the proaggregatory actions of low PGE2 concentration. In contrast, the prostacyclin receptor (IP) mediates the inhibitory effect of higher PGE2 concentrations. Furthermore, the relative activation of these two receptors, EP3 and IP, regulates the intracellular level of cAMP and in this way conditions the response of the platelet to aggregating agents. Consistent with these findings, loss of the EP3 receptor in a model of venous inflammation protects against formation of intravascular clots. Our results suggest that local production of PGE2 during an inflammatory process can modulate ensuing platelet responses.

Animals↗
PubMed2001

Receptors for prostaglandin E(2) that regulate cellular immune responses in the mouse.

Production of prostaglandin E(2) (PGE(2)) is enhanced during inflammation, and this lipid mediator can dramatically modulate immune responses. There are four receptors for PGE(2) (EP1-EP4) with unique patterns of expression and different coupling to intracellular signaling pathways. To identify the EP receptors that regulate cellular immune responses, we used mouse lines in which the genes encoding each of the four EP receptors were disrupted by gene targeting. Using the mixed lymphocyte response (MLR) as a model cellular immune response, we confirmed that PGE(2) has potent antiproliferative effects on wild-type responder cells. The absence of either the EP1 or EP3 receptors did not alter the inhibitory response to PGE(2) in the MLR. In contrast, when responder cells lacked the EP2 receptor, PGE(2) had little effect on proliferation. Modest resistance to PGE(2) was also observed in EP4-/- responder cells. Reconstitution experiments suggest that EP2 receptors primarily inhibit the MLR through direct actions on T cells. Furthermore, PGE(2) modulates macrophage function by activating the EP4 receptor and thereby inhibiting cytokine release. Thus, PGE(2) regulates cellular immune responses through distinct EP receptors on different immune cell populations: EP2 receptors directly inhibit T cell proliferation while EP2 and EP4 receptors regulate antigen presenting cells functions.

Animals↗
PubMed2000

The breast cancer susceptibility gene BRCA1 is required for subnuclear assembly of Rad51 and survival following treatment with the DNA cross-linking agent cisplatin.

Mutations in breast cancer tumor susceptibility genes, BRCA1 and BRCA2, predispose women to early onset breast cancer and other malignancies. The Brca genes are involved in multiple cellular processes in response to DNA damage including checkpoint activation, gene transcription, and DNA repair. Biochemical interaction with the recombinational repair protein Rad51 (Scully, R., Chen, J., Ochs, R. L., Keegan, K., Hoekstra, M., Feunteun, J., and Livingston, D. M. (1997) Cell 90, 425-435), as well as genetic evidence (Moynahan, M. E., Chiu, J. W., Koller, B. H., and Jasin, M. (1999) Mol. Cell 4, 511-518 and Snouwaert, J. N., Gowen, L. C., Latour, A. M., Mohn, A. R., Xiao, A., DiBiase, L., and Koller, B. H. (1999) Oncogene 18, 7900-7907), demonstrates that Brca1 is involved in recombinational repair of DNA double strand breaks. Using isogenic Brca1(+/+) and brca1(-/-) mouse embryonic stem (ES) cell lines, we investigated the role of Brca1 in the cellular response to two different categories of DNA damage: x-ray induced damage and cross-linking damage caused by the chemotherapeutic agent, cisplatinum. Immunoflourescence studies with normal and brca1(-/-) mutant mouse ES cell lines indicate that Brca1 promotes assembly of subnuclear Rad51 foci following both types of DNA damage. These foci are likely to be oligomeric complexes of Rad51 engaged in repair of DNA lesions or in processes that allow cells to tolerate such lesions during DNA replication. Clonogenic assays show that brca1(-/-) mutants are 5-fold more sensitive to cisplatinum compared with wild-type cells. Our studies suggest that Brca1 contributes to damage repair and/or tolerance by promoting assembly of Rad51. This function appears to be shared with Brca2.

Animals↗
PubMed2000

Mice heterozygous for a Brca1 or Brca2 mutation display distinct mammary gland and ovarian phenotypes in response to diethylstilbestrol.

Women who inherit mutations in the breast cancer susceptibility genes, BRCA1 and BRCA2, are predisposed to the development of breast and ovarian cancer. We used mice with a Brca1 mutation on a BALB/cJ inbred background (BALB/cB1+/- mice) or a Brca2 genetic alteration on the 129/SvEv genetic background (129B2+/- mice) to investigate potential gene-environment interactions between defects in these genes and treatment with the highly estrogenic compound diethylstilbestrol (DES). Beginning at 3 weeks of age, BALB/cB1+/-, 129B2+/-, and wild-type female mice were fed a control diet or a diet containing 640 ppb DES for 26 weeks. DES treatment caused vaginal epithelial hyperplasia and hyperkeratosis, uterine inflammation, adenomyosis, and fibrosis, as well as oviductal smooth muscle hypertrophy. The severity of the DES response was mouse strain specific. The estrogen-responsive 129/SvEv strain exhibited an extreme response in the reproductive tract, whereas the effect in BALB/cJ and C3H/HeN(MMTV-) mice was less severe. The Brca1 and Brca2 genetic alterations influenced the phenotypic response of BALB/cJ and 129/SvEv inbred strains, respectively, to DES in the mammary gland and ovary. The mammary duct branching morphology was inhibited in DES-treated BALB/cB1+/- mice compared with similarly treated BALB/cB1+/+ littermates. In addition, the majority of BALB/cB1+/- mice had atrophied ovaries, whereas wild-type littermates were largely diagnosed with arrested follicular development. The mammary ductal architecture in untreated 129B2+/- mice revealed a subtle inhibited branching phenotype that was enhanced with DES treatment. However, no significant differences were observed in ovarian pathology between 129B2+/+ and 129B2+/- mice. These data suggest that estrogenic compounds may modulate mammary gland or ovarian morphology in BALB/cB1+/- and 129B2+/- mice. These observations are consistent with the hypothesis that compromised DNA repair processes in cells harboring Brca1 or Brca2 mutations lead to inhibited growth and differentiation compared with the proliferative response of wild-type cells to DES treatment.

Animals↗
PubMed2000

Cardiovascular responses to the isoprostanes iPF(2alpha)-III and iPE(2)-III are mediated via the thromboxane A(2) receptor in vivo.

BACKGROUND: Isoprostanes (iPs) are free radical-catalyzed products of arachidonic acid that reflect lipid peroxidation in vivo. Several iPs exert biological effects in vitro and may contribute to the functional consequences of oxidant stress. For example, iPF(2alpha)-III (8-iso PGF(2alpha)) and iPE(2)-III modulate platelet function and vascular tone. Although these effects are blocked by antagonists of the receptor (TP) for the cyclooxygenase product thromboxane A(2), it has been speculated that the iPs may activate a receptor related to, but distinct from, the TP. METHODS AND RESULTS: Transgenic mice (TPOEs) were generated in which the TP-beta isoform was under the control of the preproendothelin promoter. They overexpressed TP-beta in the vasculature but not in platelets and exhibited an exaggerated pressor response to infused iPF(2alpha)-III compared with wild-type mice. This was blocked by TP antagonism. The platelet response to the iP was unaltered in TPOEs compared with wild-type mice. By contrast, both the pressor response to iPF(2alpha)-III and its effects on platelet function were abolished in mice lacking the TP gene. This was also true of the effects of infused iPE(2)-III on mean arterial pressure and platelet aggregation. CONCLUSIONS: Both iPF(2alpha)-III and iPE(2)-III exert their effects on platelet function and vascular tone in vivo by acting as incidental ligands at membrane TPs rather than via a distinct iP receptor. Activation of TPs by iPs may be of importance in syndromes in which cyclooxygenase activation and oxidant stress coincide, such as in atherosclerosis and reperfusion after tissue ischemia.

Angiotensin II↗
PubMed2000

Genetic factors determine the contribution of leukotrienes to acute inflammatory responses.

Leukotrienes (LT) are potent lipid mediators synthesized by the 5-lipoxygenase pathway of arachidonic acid (AA) metabolism. LT have been implicated in a broad spectrum of inflammatory processes. To investigate the influence of genetic factors on the contribution of LT to acute inflammation, we generated congenic 5-lipoxygenase-deficient 129, C57BL/6 (B6), and DBA/1Lac (DBA) mouse lines. Topical application of AA evoked a vigorous inflammatory response in 129 and DBA mice, whereas only a modest response was seen in B6 animals. The response to AA in 129 and DBA strains is LT dependent. In contrast, LT make little contribution to this response in B6 mice. AA-induced inflammation in B6 mice is prostanoid dependent, since this response was substantially reduced by treating B6 mice with a cyclooxygenase inhibitor. These data suggest that prostanoids are essential for AA-induced cutaneous inflammation in B6 mice, whereas LT are the major mediators of this response in 129 and DBA strains. In contrast, the response to AA in the peritoneal cavity is robust in the 129 and B6 strains, but was significantly blunted in DBA mice, showing that strain differences in the response to AA are tissue specific. Variations in these and other experimental models of inflammation appear to correlate directly with the ability of a particular mouse strain and a specific tissue to respond to LT, specifically LTC4. Taken together, these findings indicate that the relative contribution of prostanoids and LT to inflammatory responses is variable not only between strains but also between different tissues within these inbred mouse lines.

Acute Disease↗