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Targeted disruption of the chemokine eotaxin partially reduces antigen-induced tissue eosinophilia.

Rothenberg ME, MacLean JA, Pearlman E, Luster AD, Leder P - J. Exp. Med. (1997)

Bottom Line: Furthermore, it remains unclear why there is constitutive expression of eotaxin in healthy states in the absence of eosinophilic inflammation.To begin to determine the significance of eotaxin at baseline and during eosinophil-mediated disease processes, we have used targeted gene disruption to generate mice that are deficient in eotaxin.These results indicate a contributory role for eotaxin in the generation of peripheral blood and antigen-induced tissue eosinophilia.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.

ABSTRACT
The chemokines are a large group of chemotactic cytokines that regulate leukocyte trafficking and have recently been shown to inhibit human immunodeficiency virus entry into cells. Eotaxin is a C-C chemokine implicated in the recruitment of eosinophils in a variety of inflammatory disorders and, unlike all other eosinophil chemoattractants, is eosinophil specific. However, given the large number of chemoattractants that have activities on eosinophils, it is unclear whether eotaxin has an important role in vivo. Furthermore, it remains unclear why there is constitutive expression of eotaxin in healthy states in the absence of eosinophilic inflammation. To begin to determine the significance of eotaxin at baseline and during eosinophil-mediated disease processes, we have used targeted gene disruption to generate mice that are deficient in eotaxin. Such mice demonstrate that eotaxin enhances the magnitude of the early (but not late) eosinophil recruitment after antigen challenge in models of asthma and stromal keratitis. Surprisingly, a role for eotaxin in regulating the constitutive number of eosinophils in the peripheral circulation is also demonstrated. These results indicate a contributory role for eotaxin in the generation of peripheral blood and antigen-induced tissue eosinophilia.

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Allergen induced airway eosinophilia. Mice were sensitized  systemically to OVA and underwent inhaled OVA challenge. At 18 h after allergen challenge, the lungs were assessed for eotaxin mRNA expression (A) and the eosinophil count in the bronchoalveolar fluid (B).  Northern blot analysis of total RNA evaluating eotaxin expression in eotaxin  (−/−) and wild-type mice (+/+). The hybridization of a 28S  rRNA cDNA probe is also shown. Each lane represents a different  mouse. In (B), the number of eosinophils in the lung fluid is shown as  mean ± SEM for wild-type (n = 10), eotaxin  (n = 13), or control  unsensitized mice (n = 3); P = 0.005 between +/+ and −/−.
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Figure 3: Allergen induced airway eosinophilia. Mice were sensitized systemically to OVA and underwent inhaled OVA challenge. At 18 h after allergen challenge, the lungs were assessed for eotaxin mRNA expression (A) and the eosinophil count in the bronchoalveolar fluid (B). Northern blot analysis of total RNA evaluating eotaxin expression in eotaxin (−/−) and wild-type mice (+/+). The hybridization of a 28S rRNA cDNA probe is also shown. Each lane represents a different mouse. In (B), the number of eosinophils in the lung fluid is shown as mean ± SEM for wild-type (n = 10), eotaxin (n = 13), or control unsensitized mice (n = 3); P = 0.005 between +/+ and −/−.

Mentions: Eotaxin has been implicated in the recruitment of eosinophils into the lungs following allergen challenge (5, 6, 11). Therefore, it was important also to determine whether the deletion of eotaxin affected the recruitment of eosinophils into the lung during experimental allergic airway disease. When mice are sensitized to intraperitoneal OVA and then challenged with inhaled OVA, eotaxin lung mRNA is known to be induced rapidly (with peak expression at 3–6 h) and is accompanied by the development of an eosinophil-dependent allergic airway disease (6, 11, 20). At 18 h after allergen challenge, eotaxin mRNA was readily detectable in the lungs of wild-type mice, but not detectable in eotaxin mice (Fig. 3 A). This confirmed that the eotaxin gene was indeed inactivated. At 18 h after the allergen challenge, the number of cells in the BAL fluid was assessed. No significant differences in the lymphocyte, neutrophil, or macrophage cell counts were detectable (data not shown). However, eosinophil numbers were reduced by 70% in the eotaxin mice compared with identically treated wildtype mice (6.6 ± 1.7 × 104 versus 2.1 ± 0.5 × 105, respectively, P = 0.005) (Fig. 3 B). This observation demonstrated that eotaxin was important in the early recruitment of eosinophils to the lungs in this model.


Targeted disruption of the chemokine eotaxin partially reduces antigen-induced tissue eosinophilia.

Rothenberg ME, MacLean JA, Pearlman E, Luster AD, Leder P - J. Exp. Med. (1997)

Allergen induced airway eosinophilia. Mice were sensitized  systemically to OVA and underwent inhaled OVA challenge. At 18 h after allergen challenge, the lungs were assessed for eotaxin mRNA expression (A) and the eosinophil count in the bronchoalveolar fluid (B).  Northern blot analysis of total RNA evaluating eotaxin expression in eotaxin  (−/−) and wild-type mice (+/+). The hybridization of a 28S  rRNA cDNA probe is also shown. Each lane represents a different  mouse. In (B), the number of eosinophils in the lung fluid is shown as  mean ± SEM for wild-type (n = 10), eotaxin  (n = 13), or control  unsensitized mice (n = 3); P = 0.005 between +/+ and −/−.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2196140&req=5

Figure 3: Allergen induced airway eosinophilia. Mice were sensitized systemically to OVA and underwent inhaled OVA challenge. At 18 h after allergen challenge, the lungs were assessed for eotaxin mRNA expression (A) and the eosinophil count in the bronchoalveolar fluid (B). Northern blot analysis of total RNA evaluating eotaxin expression in eotaxin (−/−) and wild-type mice (+/+). The hybridization of a 28S rRNA cDNA probe is also shown. Each lane represents a different mouse. In (B), the number of eosinophils in the lung fluid is shown as mean ± SEM for wild-type (n = 10), eotaxin (n = 13), or control unsensitized mice (n = 3); P = 0.005 between +/+ and −/−.
Mentions: Eotaxin has been implicated in the recruitment of eosinophils into the lungs following allergen challenge (5, 6, 11). Therefore, it was important also to determine whether the deletion of eotaxin affected the recruitment of eosinophils into the lung during experimental allergic airway disease. When mice are sensitized to intraperitoneal OVA and then challenged with inhaled OVA, eotaxin lung mRNA is known to be induced rapidly (with peak expression at 3–6 h) and is accompanied by the development of an eosinophil-dependent allergic airway disease (6, 11, 20). At 18 h after allergen challenge, eotaxin mRNA was readily detectable in the lungs of wild-type mice, but not detectable in eotaxin mice (Fig. 3 A). This confirmed that the eotaxin gene was indeed inactivated. At 18 h after the allergen challenge, the number of cells in the BAL fluid was assessed. No significant differences in the lymphocyte, neutrophil, or macrophage cell counts were detectable (data not shown). However, eosinophil numbers were reduced by 70% in the eotaxin mice compared with identically treated wildtype mice (6.6 ± 1.7 × 104 versus 2.1 ± 0.5 × 105, respectively, P = 0.005) (Fig. 3 B). This observation demonstrated that eotaxin was important in the early recruitment of eosinophils to the lungs in this model.

Bottom Line: Furthermore, it remains unclear why there is constitutive expression of eotaxin in healthy states in the absence of eosinophilic inflammation.To begin to determine the significance of eotaxin at baseline and during eosinophil-mediated disease processes, we have used targeted gene disruption to generate mice that are deficient in eotaxin.These results indicate a contributory role for eotaxin in the generation of peripheral blood and antigen-induced tissue eosinophilia.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.

ABSTRACT
The chemokines are a large group of chemotactic cytokines that regulate leukocyte trafficking and have recently been shown to inhibit human immunodeficiency virus entry into cells. Eotaxin is a C-C chemokine implicated in the recruitment of eosinophils in a variety of inflammatory disorders and, unlike all other eosinophil chemoattractants, is eosinophil specific. However, given the large number of chemoattractants that have activities on eosinophils, it is unclear whether eotaxin has an important role in vivo. Furthermore, it remains unclear why there is constitutive expression of eotaxin in healthy states in the absence of eosinophilic inflammation. To begin to determine the significance of eotaxin at baseline and during eosinophil-mediated disease processes, we have used targeted gene disruption to generate mice that are deficient in eotaxin. Such mice demonstrate that eotaxin enhances the magnitude of the early (but not late) eosinophil recruitment after antigen challenge in models of asthma and stromal keratitis. Surprisingly, a role for eotaxin in regulating the constitutive number of eosinophils in the peripheral circulation is also demonstrated. These results indicate a contributory role for eotaxin in the generation of peripheral blood and antigen-induced tissue eosinophilia.

Show MeSH
Related in: MedlinePlus