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Surfactant protein D alters allergic lung responses in mice and human subjects

https://doi.org/10.1016/j.jaci.2008.02.011Get rights and content

Background

Surfactant protein (SP) D has been proposed to be protective in allergic airway responses.

Objective

We aimed to determine the effect of SP-D deficiency on murine and human airway allergy.

Methods

Immunologic responses of SP-D gene–deficient mice (Sftpd−/−) at baseline and after 4 intranasal Aspergillus fumigatus exposures were assessed. In addition, the significance of a single nucleotide polymorphism (Met11Thr) in the human SP-D gene (known to decrease SP-D function) was investigated.

Results

Macrophage and neutrophil bronchoalveolar lavage fluid levels and large airway mucus production were increased in naive Sftpd−/− mice in association with increased lung CCL17 levels and CD4+ T cell numbers. TH2-associated antibody levels (IgG1 and IgE) were significantly lower in 4- to 5-week-old Sftpd−/− mice (P < .05). Accordingly, naive Sftpd−/− splenocytes released significantly less IL-4 and IL-13 on anti-CD3/CD28 stimulation (P < .01). After intranasal allergen exposures, a modest decrease in bronchoalveolar lavage fluid eosinophilia and IL-13 levels was observed in Sftpd−/− mice compared with values seen in wild-type mice in association with decreased airway resistance (P < .01). A single nucleotide polymorphism in the SFTPD gene, affecting SP-D levels and pathogen binding, was associated with decreased atopy in black subjects and potentially lower asthma susceptibility in white subjects.

Conclusion

Sftpd−/− mice have an impaired systemic TH2 response at baseline and reduced inflammation and airway responses after allergen exposure. Translational studies revealed that a polymorphism in the SFTPD gene was associated with lower atopy and possibly asthma susceptibility. Taken together, these results support the hypothesis that SP-D–dependent innate immunity influences atopy and asthma.

Section snippets

Patients

The inclusion criteria are as follows: (1) a diagnosis of asthma and (2) age greater than 5 years and less than 18 years. The exclusion criteria are as follows: (1) presence of a comorbid lung condition and (2) dependency on oral steroids or an immunosuppressive agent for a medical condition other than asthma. These children subsequently underwent skin prick testing to a panel of 11 relevant environmental antigens indigenous to the Ohio valley (Greer Laboratories, Lenoir, NC).

The patients in

Increased leukocytes in the lungs of naive SP-D–deficient mice

To uncover early events associated with the development of pulmonary inflammation, we focused our study on 4- to 5-week-old Sftpd−/− mice. A significant increase in cells recovered from the BALF of Sftpd−/− mice was already observed at 4 to 5 weeks of age (Fig 1, A). More than 97% of these BALF cells were macrophages. Although neutrophils were rare in naive wild-type mice (<1%), the percentage of BALF neutrophils was significantly higher in Sftpd−/− mice (Fig 1, B). Similarly, mucus-producing

Discussion

In the present study a human SP-D mutation (Met11Thr) that inhibits SP-D binding to pathogens14 was associated with decreased atopy and potentially asthma susceptibility. A recent German study concludes that none of the 3 known amino acid variants in SP-D are associated with bronchial asthma.27 However, the German control population was randomly selected and did not exclude all control subjects with a history of asthma.27 In the present study the control subjects were carefully selected but

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    Supported in part by a grant from the Mechanism of Asthma and Allergic Inflammation (MAAI) 2005 Interest Section Award (E.B.B.), MECEH-Institutional NIEHS T32 ES10957-03 and CCHMC-Institutional NICHD T32 HD43005-01 grants (M.D.S.), as well as National Institutes of Health grants HL-63329 (J.A.W.), R01 AI42242, HL-076383, and AI057803 (M.E.R.).

    Disclosure of potential conflict of interest: N. Wang has received research support from the National Institutes of Health. J. A. Whitsett has a US patent (no. 6,838,429; surfactant protein D and emphysema), has received research support from the National Institutes of Health; and is on the speakers' bureau for Abbott Laboratories. M. E. Rothenberg has consulting arrangements with Ception Therapeutics, GlaxoSmith-Kline, and MedaCorp; owns stock in Ception Therapeutics; is on the speakers' bureau for Merck; and has received honoraria from GlaxoSmithKline, Ception Therapeutics, and Merck. The rest of the authors have declared that they have no conflict of interest.

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