Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2015 Mar 1;308(5):L485-93.
doi: 10.1152/ajplung.00227.2014. Epub 2015 Jan 9.

Airway responsiveness in CD38-deficient mice in allergic airway disease: studies with bone marrow chimeras

Alonso G P Guedes  1 , Joseph A Jude  2 , Jaime Paulin  3 , Laura Rivero-Nava  4 , Hirohito Kita  5 , Frances E Lund  6 , Mathur S Kannan  7
Affiliations

Airway responsiveness in CD38-deficient mice in allergic airway disease: studies with bone marrow chimeras

Alonso G P Guedes et al. Am J Physiol Lung Cell Mol Physiol. .

Abstract

CD38 is a cell-surface protein involved in calcium signaling and contractility of airway smooth muscle. It has a role in normal airway responsiveness and in airway hyperresponsiveness (AHR) developed following airway exposure to IL-13 and TNF-α but appears not to be critical to airway inflammation in response to the cytokines. CD38 is also involved in T cell-mediated immune response to protein antigens. In this study, we assessed the contribution of CD38 to AHR and inflammation to two distinct allergens, ovalbumin and the epidemiologically relevant environmental fungus Alternaria. We also generated bone marrow chimeras to assess whether Cd38(+/+) inflammatory cells would restore AHR in the CD38-deficient (Cd38(-/-)) hosts following ovalbumin challenge. Results show that wild-type (WT) mice develop greater AHR to inhaled methacholine than Cd38(-/-) mice following challenge with either allergen, with comparable airway inflammation. Reciprocal bone marrow transfers did not change the native airway phenotypic differences between WT and Cd38(-/-) mice, indicating that the lower airway reactivity of Cd38(-/-) mice stems from Cd38(-/-) lung parenchymal cells. Following bone marrow transfer from either source and ovalbumin challenge, the phenotype of Cd38(-/-) hosts was partially reversed, whereas the airway phenotype of the WT hosts was preserved. Airway inflammation was similar in Cd38(-/-) and WT chimeras. These results indicate that loss of CD38 on hematopoietic cells is not sufficient to prevent AHR and that the magnitude of airway inflammation is not the predominant underlying determinant of AHR in mice.

Keywords: Alternaria; CD38; allergic airway disease; bone marrow chimeras.

PubMed Disclaimer

Figures

Fig. 1.
Fig. 1.
Changes in lung resistance (RL) following inhaled methacholine (MCh) in mice. A: changes in RL in response to different doses of MCh in naïve wild-type (WT) and CD38-deficient (Cd38−/−) mice (n = 10/group). BL, baseline. B: changes in RL in naïve WT mice (WT Naïve), WT mice primed with ovalbumin (WT Primed), and WT mice primed and intranasally challenged with ovalbumin (WT P+Ch) (n = 10/group). C: lack of changes in RL in naïve Cd38−/− mice (Cd38−/− Naïve), Cd38−/− mice primed with ovalbumin (Cd38−/− Primed), and Cd38−/− mice primed and intranasally challenged with ovalbumin (Cd38−/− P+Ch) (n = 10/group). D: comparison of MCh responsiveness in WT and Cd38−/− mice primed and challenged with ovalbumin. Values are shown as means ± SE. *P < 0.05.
Fig. 2.
Fig. 2.
MCh responsiveness in wild-type (WT) and Cd38−/− mice following intranasal challenge with the extract of Alternaria (Alt). A: changes in RL in response to different doses of MCh in naïve WT and Cd38−/− mice (n = 6/group). B–D: changes in RL in response to different doses of MCh in WT and Cd38−/− mice following intranasal challenge with 10 mg/ml (B, n = 6/group), 50 mg/ml (C, n = 6/group), or 100 mg/ml (D, n = 6/group) of the Alternaria extract. Values are shown as means ± SE. *P < 0.05.
Fig. 3.
Fig. 3.
Total and differential cell numbers in bronchoalveolar lavage fluid (BALF) and evaluation of parenchymal inflammation in WT and Cd38−/− mice. A: total cells in naïve mice (WT Naïve and Cd38−/− Naïve), in mice primed with ovalbumin (WT Primed and Cd38−/− Primed), and in mice following ovalbumin sensitization and challenge (WT P+Ch and Cd38−/− P+Ch) (n = 7–10/group). B: total cells in naïve mice, in mice following intranasal challenge with 50 mg/ml (Cd38−/−-Alt 50 and WT-Alt 50), or 100 mg/ml (Cd38−/−-Alt 100 and WT-Alt 100) Alternaria extract (n = 6/group). C: differential cell counts in BALF of mice following intranasal challenge with 50 mg/ml or 100 mg/ml Alternaria extract (n = 6/group). D: lung parenchymal inflammation following 50 mg/ml intranasal Alternaria challenge in WT and Cd38−/− mice (n = 6/group). Values obtained from individual mice (A and B only) along with group means ± SE (A–D) are shown. Subjective inflammation scores were converted to ranks during statistical analyzes (Kruskal-Wallis one-way ANOVA on ranks), and these data are shown as mean ranks of inflammation scores. Statistical significance is denoted with superscripted letters (a, b, c) above group values such that treatment groups without common letters are significantly different (P < 0.05). Note significantly greater airway inflammation, as indicated by higher BALF cell numbers and parenchymal inflammation scores, in WT and Cd38−/− mice following allergen challenge compared with respective naïve controls.
Fig. 4.
Fig. 4.
Cytokine/chemokine concentrations in the BALF in WT and Cd38−/− mice. A: IL-5, IL-13, and eotaxin-2 levels in the BALF obtained from naïve mice and from mice following ovalbumin sensitization and challenge (WT P+Ch and Cd38−/− P+Ch). Note significant elevations in the levels of IL-13 and eotaxin-2 in WT and Cd38−/− mice following ovalbumin challenge (n = 10/group). B: IL-5, IL-13, and eotaxin-2 levels in the BALF obtained from naïve mice and from mice following challenge with 50 mg/ml Alternaria extract (n = 6/group). Values are shown as means ± SE. Within each cytokine/chemokine, statistical significance is denoted with superscripted letters (a, b, c) above group values such that treatment groups without common letters are significantly different (P < 0.05).
Fig. 5.
Fig. 5.
Effect of irradiation and bone marrow transfer on airway responsiveness to inhaled MCh in naïve WT and Cd38−/− mice. A: changes in RL in response to increasing doses of inhaled MCh in naïve intact WT mice or in naïve chimeric WT mice transferred with WT bone marrow (WT BM) or Cd38−/− bone marrow (Cd38−/− BM). Note that MCh responsiveness in the WT mice is unchanged following irradiation and transfer of WT bone marrow but is slightly decreased following irradiation and transfer of Cd38−/− bone marrow. B: changes in RL in response to increasing doses of inhaled MCh in naïve intact Cd38−/− mice or in naïve chimeric Cd38−/− mice following transfer of Cd38−/− bone marrow or WT bone marrow. Note significant attenuation of MCh responsiveness following transfer of both types of bone marrow. C: MCh responsiveness in naive WT chimeras and Cd38−/− chimeras. Note that MCh responsiveness is greater in the WT chimeras compared with Cd38−/− chimeras. *P < 0.05. Values are shown as means ± SE, n = 5–10/group.
Fig. 6.
Fig. 6.
Changes in RL in response to different doses of MCh in WT and Cd38−/− mice following bone marrow transfer and ovalbumin sensitization and challenge. A: changes in RL measured in ovalbumin-sensitized and -challenged WT (WT P+Ch) and Cd38−/− (Cd38−/− P+Ch) mice. B: MCh responsiveness in chimeric mice sensitized and challenged with ovalbumin. Note lower RL in response to the highest dose of MCh in the chimeric Cd38−/− mice compared with the chimeric WT mice. C: MCh responsiveness in intact and chimeric WT mice following ovalbumin sensitization and challenge. Note similar RL regardless of whether the WT mice received bone marrow from Cd38−/− or WT mice. D: MCh responsiveness in intact and chimeric Cd38−/− mice following ovalbumin sensitization and challenge. Note the significantly higher MCh responsiveness in chimeric Cd38−/− mice transferred with Cd38−/− or WT bone marrow compared with the intact mice. E: total cell numbers (individual mice and groups mean ± SE) in BALF obtained from naïve WT and Cd38−/− mice following radiation and bone marrow transfer. Note significant elevations in cell numbers in ovalbumin-sensitized and -challenged mice regardless of the source of bone marrow. Data are shown as means ± SE (n = 5/group). *P < 0.05.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Ammit AJ, Hoffman RK, Amrani Y, Lazaar AL, Hay DW, Torphy TJ, Penn RB, Panettieri RA Jr. Tumor necrosis factor-alpha-induced secretion of RANTES and interleukin-6 from human airway smooth-muscle cells. Modulation by cyclic adenosine monophosphate. Am J Respir Cell Mol Biol 23: 794–802, 2000. - PubMed
    1. Berkman N, Krishnan VL, Gilbey T, Newton R, O'Connor B, Barnes PJ, Chung KF. Expression of RANTES mRNA and protein in airways of patients with mild asthma. Am J Respir Crit Care Med 154: 1804–1811, 1996. - PubMed
    1. Brightling CE, Ammit AJ, Kaur D, Black JL, Wardlaw AJ, Hughes JM, Bradding P. The CXCL10/CXCR3 axis mediates human lung mast cell migration to asthmatic airway smooth muscle. Am J Respir Crit Care Med 171: 1103–1108, 2005. - PubMed
    1. Bush RK, Prochnau JJ. Alternaria-induced asthma. J Allergy Clin Immunol 113: 227–234, 2004. - PubMed
    1. Cockayne DA, Muchamuel T, Grimaldi JC, Muller-Steffner H, Randall TD, Lund FE, Murray R, Schuber F, Howard MC. Mice deficient for the ecto-nicotinamide adenine dinucleotide glycohydrolase CD38 exhibit altered humoral immune responses. Blood 92: 1324–1333, 1998. - PubMed

Publication types

MeSH terms