Surfactant protein for the prevention and diagnosis of pulmonary emphysema

An emphysema and active technology, applied in the field of biologically active proteins, can solve the problems of unidentified surfactant proteins, unclear effects, and unclear elaboration of SP-D

Inactive Publication Date: 2005-04-27
CHILDRENS HOSPITAL MEDICAL CENT CINCINNATI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Therefore, additional surfactant proteins that play a role in surfactant regulation have not been identified
Also, at this point the exact role of SP-D in normal lung function has not been clearly articulated and its role in disease or disease susceptibility is unclear

Method used

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  • Surfactant protein for the prevention and diagnosis of pulmonary emphysema
  • Surfactant protein for the prevention and diagnosis of pulmonary emphysema
  • Surfactant protein for the prevention and diagnosis of pulmonary emphysema

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0056] Construction of SP-D(- / -) knockout mice

[0057] SP-D(- / -) mice were generated by targeted gene inactivation. Integration of the pGKneo targeting vector containing sequences from exon 2 of the SP-D gene produces a deletion of the second exon of the SP-D gene, which includes removal of the initiation methionine and translation initiation sequence. The sequence of exons 1 and 2 of the mouse SP-D gene can be found under Genebank accession number AF047741. The target was designed using pGKneo by first subcloning a 5.1-kb blunt-ended KpnI-tailed HindIII genomic fragment encoding intron 2 to exon 6 into the KpnI site between the neomycin resistance cassette and the thymidine kinase cassette to the carrier. Subsequently, an XhoI linker was attached to the tail of a 1.5-kb genomic PstI fragment containing part of intron I and cloned into the XhoI site 5' of the neomycin resistance cassette. Eight of the 104 ES clones subjected to the double selection process were correctly o...

Embodiment 2

[0064] Example 2 demonstrates the effect on phospholipid levels. Alveolar and tissue phospholipid levels, particularly phosphatidylcholine pool levels, were significantly increased, while total bronchoalveolar lavage (BAL) protein levels remained unchanged.

[0065] Example 2

[0066] Phospholipid levels in SP-D(- / -) mice

[0067] Alveolar, tissue and total saturated phosphatidylcholine (Sat-PC) (p3 H) Choline incorporation into whole lung Sat-PC is slightly increased 8 hours after injection, and incorporation is approximately 20% greater in SP-D(- / -) mice (p<0.05).

Embodiment 3

[0070] Decrease of SP-A level in SP-D(- / -) mice

[0071]No differences in SP-B and SP-C mRNA or protein were observed in SP-D(- / -) mice. In contrast, Northern hybridization and hybridization to the SP-A probe of total lung RNA from SP-D(+ / +), SP-D(+ / -), and SP-D(- / -) mice showed SP-A mRNA was reduced in SP-D(- / -) mice. Consistent with the reduction in SP-A mRNA, BAL SP-A protein was significantly reduced by approximately 25% in SP-D(- / -) mice as assessed by Western blot analysis of alveolar lavage from 3 mice.

[0072] Thus, SP-D plays a role in the regulation of SP-A production. Because SP-A is involved in host defense in the lung, SP-D can affect host defense in two ways. By upregulating SP-A production and by directly interacting with immune and microbial cells.

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Abstract

Surfactant protein D (SP-D) is a 43-kDa member of the collectin family of collagenous lectin domain-containing proteins that is expressed in epithelial cells of the lung. The SP-D gene was targeted by homologous recombination in embryonic stem cells that were used to produce SP-D (- / -) mice. The SP-D (- / -) deficiency caused inflammation, increased oxidant production by isolated alveolar macrophages, abnormal surfactant structure and levels, and decreased SP-A expression. Therefore, disclosed is the SP-D (- / -) mouse as an excellent model for emphysema. Also included are models for testing emphysema therapies in the mouse model, methods for using SP-D protein or DNA as a treatment for emphysema and pulmonary infections, and diagnosis.

Description

[0001] Government Interest in the Invention [0002] Certain aspects of the invention disclosed herein were made with US Government support under grants HL 41320, SCOR HL 56387, HL 28623, HL 58795, and HL03905 from the National Institutes of Health. The US Government has certain rights in these aspects of the invention. field of invention [0003] The present invention generally relates to the field of biologically active proteins. More specifically, the present invention relates to the SP-D protein involved in lung surfactant homeostasis and structure and alveolar structure in the lung, and SP-D (- / -) null (null) mice. Background of the invention [0004] Pulmonary surfactant is indispensable for normal lung mechanics and gas exchange in the lungs. Lung surfactant is produced by type II epithelial cells and consists of a phospholipid component that confers the surfactant's ability to lower surface tension in the lung. In addition, there are proteins related to surface-ac...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K48/00A01K67/027A61K35/76A61K38/00A61P9/00A61P11/00A61P19/04A61P29/00A61P31/00A61P31/04A61P31/10A61P31/12A61P31/14A61P31/16A61P31/20A61P31/22A61P37/06A61P37/08A61P39/04A61P43/00C07K14/47C07K14/785C12N15/85
CPCA01K2217/075C12N15/8509A01K2267/0368C07K14/4726A01K2227/105A01K67/0275A01K2217/05A01K67/0276A01K2267/03A01K2267/0337A61K38/00C07K14/785A61P11/00A61P19/04A61P29/00A61P31/00A61P31/04A61P31/10A61P31/12A61P31/14A61P31/16A61P31/20A61P31/22A61P37/06A61P37/08A61P39/04A61P43/00A61P9/00
Inventor 杰弗里·A·惠特塞特
Owner CHILDRENS HOSPITAL MEDICAL CENT CINCINNATI
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