A nonredundant role for mouse Serpinb3a in the induction of mucus production in asthma.
BACKGROUND
Asthma is a major public health burden worldwide. Studies from our group and others have demonstrated that SERPINB3 and SERPINB4 are induced in patients with asthma; however, their mechanistic role in asthma has yet to be determined.


OBJECTIVE
To evaluate the role of Serpin3a, the murine homolog of SERPINB3 and SERPINB4, in asthma.


METHODS
We studied wild-type Balb/c and Serpinb3a-null mice in house dust mite or IL-13-induced asthma models and evaluated airway hyperresponsiveness, inflammation, and goblet cell hyperplasia.


RESULTS
Airway hyperresponsiveness and goblet cell hyperplasia were markedly attenuated in the Serpinb3a-null mice compared with the wild-type mice after allergen challenge, with minimal effects on inflammation. Expression of sterile alpha motif pointed domain containing v-ets avian erythroblastosis virus E26 oncogene homolog transcription factor (SPDEF), a transcription factor that mediates goblet cell hyperplasia, was decreased in the absence of Serpinb3a. IL-13-treated Serpinb3a-null mice showed attenuated airway hyperresponsiveness, inflammation, and mucus production.


CONCLUSIONS
Excessive mucus production and mucus plugging are key pathologic features of asthma, yet the mechanisms responsible for mucus production are not well understood. Our data reveal a novel nonredundant role for Serpinb3a in mediating mucus production through regulation of SPDEF expression. This pathway may be used to target mucus hypersecretion effectively.
Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio 45229, USA.
Umasundari
U
Sivaprasad
David J
DJ
Askew
Mark B
MB
Ericksen
Aaron M
AM
Gibson
Matthew T
MT
Stier
Eric B
EB
Brandt
Stacey A
SA
Bass
Michael O
MO
Daines
Jamila
J
Chakir
Keith F
KF
Stringer
Susan E
SE
Wert
Jeffrey A
JA
Whitsett
Timothy D
TD
Le Cras
Marsha
M
Wills-Karp
Gary A
GA
Silverman
Gurjit K
GK
Khurana Hershey
D000818:Animals; D001249:Asthma / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid; D002469:Cell Separation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000276:immunology; D020397:Goblet Cells / Q000276:immunology / Q000378:metabolism; D007073:Immunoglobulin E / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009093:Mucus / Q000276:immunology* / Q000378:metabolism; D050783:Proto-Oncogene Proteins c-ets / Q000096:biosynthesis / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015843:Serpins / Q000276:immunology* / Q000378:metabolism
D007074:Immunoglobulin G; D050783:Proto-Oncogene Proteins c-ets; D015843:Serpins; C519908:Spdef protein, mouse; D007073:Immunoglobulin E