pubmed.ncbi.nlm.nih.gov

Mast cells can promote the development of multiple features of chronic asthma in mice - PubMed

. 2006 Jun;116(6):1633-41.

doi: 10.1172/JCI25702. Epub 2006 May 18.

Affiliations

Mast cells can promote the development of multiple features of chronic asthma in mice

Mang Yu et al. J Clin Invest. 2006 Jun.

Abstract

Bronchial asthma, the most prevalent cause of significant respiratory morbidity in the developed world, typically is a chronic disorder associated with long-term changes in the airways. We developed a mouse model of chronic asthma that results in markedly increased numbers of airway mast cells, enhanced airway responses to methacholine or antigen, chronic inflammation including infiltration with eosinophils and lymphocytes, airway epithelial goblet cell hyperplasia, enhanced expression of the mucin genes Muc5ac and Muc5b, and increased levels of lung collagen. Using mast cell-deficient (Kit(W-sh/W-sh) and/or Kit(W/W-v)) mice engrafted with FcRgamma+/+ or FcRgamma-/- mast cells, we found that mast cells were required for the full development of each of these features of the model. However, some features also were expressed, although usually at less than wild-type levels, in mice whose mast cells lacked FcRgamma and therefore could not be activated by either antigen- and IgE-dependent aggregation of Fc epsilonRI or the binding of antigen-IgG1 immune complexes to Fc gammaRIII. These findings demonstrate that mast cells can contribute to the development of multiple features of chronic asthma in mice and identify both Fc Rgamma-dependent and Fc Rgamma-independent pathways of mast cell activation as important for the expression of key features of this asthma model.

PubMed Disclaimer

Figures

Figure 1
Figure 1. Airway responses following i.n. OVA challenge in a mouse model of chronic asthma.

(A) Penh responses to aerosolized methacholine 24 hours after the eighth OVA or PBS challenge. (B) Penh measured 1 hour before and 1, 3, 6, 9, 12, 15, 18, 21, and 24 hours after the ninth OVA or PBS challenge. (C) Changes in RL and (D) lung Cdyn after aerosolized methacholine administered 24 hours after the ninth OVA or PBS challenge. Data are from OVA-sensitized/challenged WBB6F1-Kit+/+ (filled circles), WBB6F1-KitW/W-v(open circles), and WBB6F1-Kit+/+ BMCMCs→KitW/W-v (gray circles) mice and PBS-treated WBB6F1-Kit+/+ (filled squares), WBB6F1-KitW/W-v (open squares), and WBB6F1-Kit+/+ BMCMCs→KitW/W-v (gray squares) mice. *P < 0.05 versus corresponding PBS-treated controls; †P < 0.05 versus OVA-sensitized/challenged KitW/W-v group. n = 8 per group (A and B); n = 4 per group (C and D).

Figure 2
Figure 2. Histology of lungs of OVA-sensitized/challenged mice 24 hours after the ninth OVA challenge.

(A–C) Toluidine blue stain demonstrating MCs (MCs within the epithelium are indicated by arrows in A and C; a submucosal MC is indicated by an arrowhead in A). Scale bar: 10 μm. (D–F) H&E staining showing perivascular and peribronchial infiltrates of inflammatory cells. Scale bar: 50 μm. (G–I) Congo red stain showing eosinophils (some indicated by arrows) and lymphocytes in the inflammatory infiltrates. Scale bar: 20 μm. (J–L) Masson trichrome stain showing hyperplasia of mucin-secreting goblet cells and subepithelial fibrosis. Black arrows indicate goblet cells, open arrows indicate collagen (stained blue), and arrowheads indicate airway smooth muscle. Scale bar: 15 μm.

Figure 3
Figure 3. Features of allergic inflammation in this chronic asthma model 24 hours after the ninth OVA or PBS challenge.

(A and B) Numbers of lung MCs (A) and eosinophils (B). (C) Serum histamine concentration. (A–C) White bars, PBS-treated group; black bars: OVA-sensitized/challenged group. **P < 0.01 or ***P < 0.001 versus corresponding PBS controls (n = 6); ††P < 0.01 or †††P < 0.001 versus group indicated (n = 6 per group). ND, not detected. (D) Numbers of leukocytes in BAL fluid from the right lungs of WBB6F1-Kit+/+ (black bars), WBB6F1-KitW/W-v (white bars), and Kit+/+ BMCMC→KitW/W-v (gray bars) mice following OVA sensitization/challenge (O) or PBS treatment (P). **P < 0.01 or ***P < 0.001 versus corresponding PBS controls (n = 8 per group); †P < 0.05, ††P < 0.01, or †††P < 0.001 versus group indicated (n = 8 per group). MON, monocytes; MAC, macrophages; PMN, neutrophils; EOS, eosinophils; LYM, lymphocytes.

Figure 4
Figure 4. Lung mRNA levels of genes encoding (A )FcR γchain and (B )T cell–specific GTPase 24 hours after the ninth OVA or PBS challenge.

White bars, PBS-treated group; black bars, OVA-sensitized/ challenged group. ***P < 0.001 versus corresponding PBS controls (n = 6 per group); †††P < 0.001 versus group indicated (n = 6 per group). Eq, equivalents.

Figure 5
Figure 5. Airway goblet cell numbers and mucin gene expression in this chronic asthma model 24 hours after the ninth OVA or PBS challenge.

(A and B) Lung mRNA levels of genes encoding mucin 5AC and mucin 5B. (C) Numbers of goblet cells along the airway epithelium. (D) Levels of lung hydroxyproline. White bars, PBS-treated group; black bars, OVA-sensitized/challenged group. ***P < 0.001 versus corresponding PBS controls; †P < 0.05, ††P < 0.01, or †††P < 0.001 versus group indicated. n = 6 per group (A–C); n = 8 per group (D).

Figure 6
Figure 6. Penh responses following i.n. OVA antigen challenge inKitW/W-v mice that had been engrafted withFcR γ–/– versusFcR γ+/+ BMCMCs.

(A) Responses to aerosolized methacholine 24 hours after the eighth OVA or PBS challenge. (B) Penh measured 1 hour before and 1, 3, 6, 9, 12, 18, and 24 hours after the ninth OVA or PBS challenge. Data are from OVA-sensitized/challenged FcRγ

+/+ BMCMCs→KitW/W-v (closed circles) and FcRγ–/– BMCMCs→KitW/W-v mice (open circles) and PBS-treated FcRγ+/+ BMCMCs→KitW/W-v (closed squares) and FcRγ–/– BMCMCs→KitW/W-v (open squares) mice. *P < 0.05 versus corresponding PBS controls; †P < 0.05 versus OVA-sensitized/challenged FcRγ–/– BMCMCs→KitW/W-v mice; ‡P < 0.05 versus values at that time point in the corresponding PBS control group; n = 6 per group.
Figure 7
Figure 7. Features of allergic inflammation in this chronic asthma model 24 hours after the ninth OVA or PBS challenge inFcRγ–/– BMCMCs→KitW/W-v mice versusFcRγ+/+ BMCMCs→KitW/W-v mice.

(A and B) Numbers of lung MCs (A) and eosinophils (B). (C) Serum histamine concentration. (A–C) White bars, PBS-treated group; black bars, OVA-sensitized/challenged group. (D) Numbers of leukocytes in BAL fluid from the right lungs of FcRγ

+/+ BMCMCs→KitW/W-v (black bars) and FcRγ–/– BMCMCs→KitW/W-v (white bars) mice. **P < 0.01 or ***P < 0.001 versus corresponding PBS controls; †P < 0.05, ††P < 0.01, or †††P < 0.001 versus group indicated (n = 6 per group).
Figure 8
Figure 8. Airway goblet cell numbers and mucin gene expression in this chronic asthma model 24 hours after the ninth OVA or PBS challenge inFcRγ–/– BMCMCs→KitW/W-v mice versusFcRγ+/+ BMCMCs→KitW/W-v mice.

(A) Numbers of goblet cells along the airway epithelium. (B and C) Lung mRNA levels of genes encoding mucin 5AC and mucin 5B. White bars, PBS-treated group; black bars, OVA-sensitized/challenged group. **P < 0.01 or ***P < 0.001 versus corresponding PBS controls; †P < 0.05 versus group indicated (n = 6 per group).

Similar articles

Cited by

References

    1. Wills-Karp M. Immunologic basis of antigen-induced airway hyperresponsiveness. Annu. Rev. Immunol. 1999;17:255–281. - PubMed
    1. Busse W.W., Lemanske R.F. Asthma. N. Engl. J. Med. 2001;344:350–362. - PubMed
    1. Umetsu D.T., McIntire J.J., Akbari O., Macaubas C., DeKruyff R.H. Asthma: an epidemic of dysregulated immunity. Nat. Immunol. 2002;3:715–720. - PubMed
    1. James A. Airway remodeling in asthma. Curr. Opin. Pulm. Med. 2005;11:1–6. - PubMed
    1. Davies D.E., Wicks J., Powell R.M., Puddicombe S.M., Holgate S.T. Airway remodeling in asthma: new insights. J. Allergy Clin. Immunol. 2003;111:215–225; quiz 226. - PubMed

Publication types

MeSH terms

Substances