Serum amyloid A is a soluble pattern recognition receptor that drives type 2 immunity.

The molecular basis for the propensity of a small number of environmental proteins to provoke allergic responses is largely unknown. Herein, we report that mite group 13 allergens of the fatty acid-binding protein (FABP) family are sensed by an evolutionarily conserved acute-phase protein, serum amyloid A1 (SAA1), that promotes pulmonary type 2 immunity. Mechanistically, SAA1 interacted directly with allergenic mite FABPs (Der p 13 and Blo t 13). The interaction between mite FABPs and SAA1 activated the SAA1-binding receptor, formyl peptide receptor 2 (FPR2), which drove the epithelial release of the type-2-promoting cytokine interleukin (IL)-33 in a SAA1-dependent manner. Importantly, the SAA1-FPR2-IL-33 axis was upregulated in nasal epithelial cells from patients with chronic rhinosinusitis. These findings identify an unrecognized role for SAA1 as a soluble pattern recognition receptor for conserved FABPs found in common mite allergens that initiate type 2 immunity at mucosal surfaces.

S100A alarmins and thymic stromal lymphopoietin (TSLP) regulation in severe asthma following bronchial thermoplasty.

RATIONALE: Severe asthma affects a small proportion of asthmatics but represents a significant healthcare challenge. Bronchial thermoplasty (BT) is an interventional treatment approach preconized for uncontrolled severe asthma after considering biologics therapy. It was showed that BT long-lastingly improves asthma control. These improvements seem to be related to the ability of BT to reduce airway smooth muscle remodeling, reduce the number of nerve fibers and to modulate bronchial epithelium integrity and behavior. Current evidence suggest that BT downregulates epithelial mucins expression, cytokine production and metabolic profile. Despite these observations, biological mechanisms explaining asthma control improvement post-BT are still not well understood. OBJECTIVES: To assess whether BT affects gene signatures in bronchial epithelial cells (BECs). METHODS: In this study we evaluated the transcriptome of cultured bronchial epithelial cells (BECs) of severe asthmatics obtained pre- and post-BT treatment using microarrays. We further validated gene and protein expressions in BECs and in bronchial biopsies with immunohistochemistry pre- and post-BT treatment. MEASUREMENTS AND MAIN RESULTS: Transcriptomics analysis revealed that a large portion of differentially expressed genes (DEG) was involved in anti-viral response, anti-microbial response and pathogen induced cytokine storm signaling pathway. S100A gene family stood out as five members of this family where consistently downregulated post-BT. Further validation revealed that S100A7, S100A8, S100A9 and their receptor (RAGE, TLR4, CD36) expressions were highly enriched in severe asthmatic BECs. Further, these S100A family members were downregulated at the gene and protein levels in BECs and in bronchial biopsies of severe asthmatics post-BT. TLR4 and CD36 protein expression were also reduced in BECs post-BT. Thymic stromal lymphopoietin (TSLP) and human ß-defensin 2 (hBD2) were significantly decreased while no significant change was observed in IL-25 and IL-33. CONCLUSIONS: These data suggest that BT might improve asthma control by downregulating epithelial derived S100A family expression and related downstream signaling pathways.

Effect of cannabis smoke condensate on human nasal epithelial cell adhesion, growth, and migration.

OBJECTIVE: When inhaled, cannabis smoke interacts with airway tissues, including the nasal mucosa, which may lead to nasal pathologies. We examined the effect of cannabis smoke condensate (CSC) on nasal epithelial cell and tissue behaviors. METHODS: Human nasal epithelial cells were exposed or not to CSC at different concentrations (1, 5, 10, and 20 %) and for different durations. Cell adhesion and viability were assessed, as well as post-wound cell migration and lactate dehydrogenase (LDH) release. RESULTS: The nasal epithelial cells showed a larger cell size and a faint nucleus following exposure to CSC, compared to that observed in that control. This was supported by fewer adherent cells present after exposure for either 1 or 24 h to 5, 15, and 20 % CSC. CSC also had a significant toxic effect by reducing cell viability after both 1 and 24 h of exposure. This toxic effect was significant even at a low concentration (1 %) of CSC. The effects on nasal epithelial cell viability were confirmed by the decrease in cell migration. After the scratch and subsequent exposure to CSC for either 6 or 24 h, a complete inhibition of nasal epithelial cell migration was observed, compared to that found in the controls. CSC was toxic to the nasal epithelial cells, as the level of LDH significantly increased following cell exposure all CSC concentrations. CONCLUSION: Cannabis smoke condensate had a negative effect on several nasal epithelial cell behaviors. These findings indicate that cannabis smoke could be a threat to nasal tissues and ultimately lead to nasal and sinus disorders.

Effect of e-cigarettes on nasal epithelial cell growth, Ki67 expression, and pro-inflammatory cytokine secretion.

OBJECTIVE: Upon use, e-cigarette aerosol comes in contact with various mucosal tissues, including the nasal epithelium, which may lead to nasal pathologies. We therefore assessed the effect of e-cigarettes on nasal epithelial cell and tissue behaviours. METHODS: Human primary nasal epithelial cells and engineered 3D nasal mucosa tissues were exposed or not to either e-cigarette aerosol or standard cigarette smoke. We then evaluated cell viability and lactate dehydrogenase (LDH) activity. With the tissues analysed tissue structure, the expression of Ki67 proliferating marker, and the secretion of pro-inflammatory cytokines by the engineered nasal mucosa. RESULTS: The nasal epithelial cells exposed to e-cigarettes displayed a larger cell size and a faint nucleus following exposure to e-cigarettes. This is supported by the increased levels of LDH activity following exposure to e-cigarettes, compared to that observed in the control. Tissues exposed to e-cigarette aerosol displayed a structural deregulation, with more large-sized cells, fewer Ki67-positive cells, and a reduced proliferation rate, compared to that observed in the non-exposed tissues. Cytokine measurements showed high levels of IL-6, IL-8, TNFα, and MCP-1, demonstrating that e-cigarettes activated pro-inflammatory cytokine responses. CONCLUSION: E-cigarette aerosol showed adverse effects on nasal epithelial cells and nasal engineered mucosa tissue. These findings indicate that e-cigarettes could be a threat to nasal tissues and may impair the innate immune function of nasal epithelial cells.

Human Bronchial Epithelial Cell-derived Factors from Severe Asthmatic Subjects Stimulate Eosinophil Differentiation.

Activated bronchial epithelial cells (BEC) release various alarmins, including thymic stromal lymphopoietin (TSLP), that drive type 2 inflammation. We hypothesize that BEC-derived factors promote in situ eosinophil differentiation and maturation, a process that is driven by an IL-5-rich microenvironment in asthmatic airways. To assess the eosinophilopoietic potential of epithelial-derived factors, eosinophil/basophil colony forming units (Eo/B-CFU) were enumerated in 14-day methylcellulose cultures of blood-derived nonadherent mononuclear cells incubated with BEC supernatants (BECSN) from healthy nonatopic controls (n = 8), mild atopic asthmatics (n = 9), and severe asthmatics (n = 5). Receptor-blocking antibodies were used to evaluate the contribution of alarmins. Modulation of the mRNA expression of transcription factors that are crucial for eosinophil differentiation was evaluated. BECSN stimulated the clonogenic expansion of eosinophil progenitors in vitro. In the presence of IL-5, Eo/B-CFU numbers were significantly greater in cocultures of BESCN from severe asthmatics compared with other groups. This was attenuated in the presence of a TSLP (but not an IL-33) receptor-blocking antibody. Recombinant human TSLP (optimal at 100 pg/ml) stimulated Eo/B-CFU growth, which was significantly enhanced in the presence of IL-5 (1 ng/ml). Overnight culture of CD34+ cells with IL-5 and TSLP synergistically increased GATA-binding factor 2 and CCAAT/enhancer-binding protein α mRNA expression. The eosinophilopoietic potential of factors derived from BEC is increased in severe asthma. Our data suggest that TSLP is a key alarmin that is produced by BECs and promotes in situ eosinophilopoiesis in a type 2-rich microenvironment.

E-Cigarette Vapor Induces an Apoptotic Response in Human Gingival Epithelial Cells Through the Caspase-3 Pathway.

Electronic cigarettes represent an increasingly significant proportion of today's consumable tobacco products. E-cigarettes contain several chemicals which may promote oral diseases. The aim of this study was to investigate the effect of e-cigarette vapor on human gingival epithelial cells. Results show that e-cigarette vapor altered the morphology of cells from small cuboidal form to large undefined shapes. Both single and multiple exposures to e-cigarette vapor led to a bulky morphology with large faint nuclei and an enlarged cytoplasm. E-cigarette vapor also increased L-lactate dehydrogenase (LDH) activity in the targeted cells. This activity was greater with repeated exposures. Furthermore, e-cigarette vapor increased apoptotic/necrotic epithelial cell percentages compared to that observed in the control. Epithelial cell apoptosis was confirmed by TUNEL assay showing that exposure to e-cigarette vapor increased apoptotic cell numbers, particularly after two and three exposures. This negative effect involved the caspase-3 pathway, the activity of which was greater with repeated exposure and which decreased following the use of caspase-3 inhibitor. The adverse effects of e-cigarette vapor on gingival epithelial cells may lead to dysregulated gingival cell function and result in oral disease. J. Cell. Physiol. 232: 1539-1547, 2017. © 2016 Wiley Periodicals, Inc.

Correlation between CCL26 production by human bronchial epithelial cells and airway eosinophils: Involvement in patients with severe eosinophilic asthma.

BACKGROUND: High pulmonary eosinophil counts are associated with asthma symptoms and severity. Bronchial epithelial cells (BECs) produce CC chemokines, notably CCL26 (eotaxin-3), which recruits and activates eosinophils from asthmatic patients. This suggests that CCL26 production by BECs might be involved in persistent eosinophilia in patients with severe asthma despite treatment with high corticosteroid doses. OBJECTIVE: We sought to determine whether CCL26 levels correlate with eosinophilia and asthma severity. METHODS: Human CC chemokine expression was assessed by means of quantitative PCR or a quantitative PCR array in vehicle- or IL-13-treated BECs. CCL26 was quantitated by means of ELISA. Immunohistochemistry analyses of CCL26 and major basic protein were done on bronchial biopsy specimens. RESULTS: IL-13 selectively induced CCL26 expression by BECs. This increase was time-dependent and more prominent in BECs from patients with severe eosinophilic asthma. CCL26 levels measured in supernatants of IL-13-stimulated BECs also increased with asthma severity as follows: patients with severe eosinophilic asthma > patients with mild asthma ≈ healthy subjects. Immunohistochemistry analyses of bronchial biopsy specimens confirmed increased levels of CCL26 in the epithelium of patients with mild and those with severe eosinophilic asthma. Tissue eosinophil counts did not correlate with CCL26 staining. However, sputum CCL26 levels significantly correlated with sputum eosinophil counts (P < .0001), suggesting that CCL26 participates in the movement of eosinophils from the tissues to the airway lumen. CONCLUSIONS: These results show a relation between CCL26 production by IL-13-stimulated BECs, sputum eosinophil counts, and asthma severity. They also suggest a role for CCL26 in the sustained inflammation observed in patients with severe eosinophilic asthma and reveal CCL26 as a potential target for treating patients with eosinophilic asthma that are refractory to classic therapies.

α2ß1 integrin regulates Th17 cell activity and its neutralization decreases the severity of collagen-induced arthritis.

Th17 cells play a critical role in the pathogenesis of rheumatoid arthritis (RA), but the mechanisms by which these cells regulate the development of RA are not fully understood. We have recently shown that α2ß1 integrin, the receptor of type I collagen, is the major collagen-binding integrin expressed by human Th17 cells. In this study, we examined the role of α2ß1 integrin in Th17-mediated destructive arthritis in the murine model of collagen-induced arthritis (CIA). We found that α2ß1 integrin is expressed on synovial Th17 cells from CIA mice and its neutralization with a specific mAb significantly reduced inflammation and cartilage degradation, and protected the mice from bone erosion. Blockade of α2ß1 integrin led to a decrease in the number of Th17 cells in the joints and to a reduction of IL-17 levels in CIA mice. This was associated with an inhibition of receptor activator of NF-κB ligand levels and osteoclast numbers, and reduction of bone loss. We further show that α2ß1 integrin is expressed on synovial Th17 cells from RA patients, and that its ligation with collagen costimulated the production of IL-17 by polarized human Th17 cells by enhancing the expression of retinoic acid receptor-related orphan receptor C through ERK and PI3K/AKT. Our findings provide the first evidence, to our knowledge, that α2ß1 integrin is an important pathway in Th17 cell activation in the pathogenesis of CIA, suggesting that its blockade can be beneficial for the treatment of RA and other Th17-associated autoimmune diseases.

Neuronal chemorepellent Semaphorin 3E inhibits human airway smooth muscle cell proliferation and migration.

BACKGROUND: Chronic airway diseases, including asthma, are characterized by increased airway smooth muscle (ASM) mass that is due in part to growth factor-mediated ASM cell proliferation and migration. However, the molecular mechanisms underlying these effects are not completely understood. Semaphorin 3E (Sema3E) has emerged as an essential mediator involved in cell migration, proliferation, and angiogenesis, although its role in ASM cell function is not investigated. OBJECTIVES: We sought to determine the expression of Sema3E receptor, plexinD1, in human ASM cells (HASMCs); effect of Sema3E on basal and platelet-derived growth factor (PDGF)-induced proliferation and migration; and underlying signaling pathways. METHODS: Expression of plexinD1 in HASMCs was studied with RT-PCR, immunostaining, and flow cytometry. The effect of Sema3E on HASMC proliferation and migration was evaluated by 5-ethynyl-2'-deoxyuridine (EdU) incorporation, cell count, and Boyden chamber assay. Sema3E-mediated intracellular signaling was investigated with fluorescent microscopy, flow cytometry, Rac1 activation, and Western blot analysis. RESULTS: HASMCs from healthy persons expressed plexinD1 more than HASMCs from asthmatic patients. Sema3E increased plexinD1 expression in HASMCs from asthmatic patients. Recombinant Sema3E inhibited PDGF-mediated HASMC proliferation and migration, which was associated with F-actin depolymerization, suppression of PDGF-induced Rac1 guanosine triphosphatase activity, and Akt and extracellular signal-regulated kinase 1 and 2 phosphorylation. Bronchial biopsies from patients with mild asthma displayed immunoreactivity of plexinD1, suggesting the potential in vivo role of Sema3E-PlexinD1 axis in HASMC function. CONCLUSION: This study provides the first evidence that Sema3E receptor is expressed and plays functional roles in HASMCs. Our data suggest a regulatory role of Sema3E in PDGF-mediated proliferation and migration, leading to downregulation of ASM remodeling.

Fibroblast growth factor-2 is a sputum remodeling biomarker of severe asthma.

OBJECTIVE: Given the large phenotypic diversity of asthma, our aim was to characterize molecular profiles related to asthma severity using selected remodeling biomarkers in induced sputum. METHODS: Induced sputum from healthy controls, patients with mild to moderate asthma and severe asthma were collected. Twelve selected biomarkers previously associated to airway remodeling such as connective tissue growth factor (CTGF), fibroblast growth factor (FGF)-2, matrix metalloproteinase (MMP)-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-12, MMP-13, procollagen type 1 and tissue inhibitor of metalloproteinase (TIMP)-1 were measured in sputum samples using ELISA or Luminex technology. FGF-2 level was also evaluated in bronchial biopsies using immunohistochemistry. RESULTS: Sputum of severe asthma was characterized by reduced percentage of macrophages and increased percentage of neutrophils and eosinophils. FGF-2, MMP-1 and TIMP-1 levels increased with asthma severity. Interestingly, only FGF-2 level inversely correlated with FEV1/FVC ratio. Although percentage of eosinophils correlated with asthma severity, it did not correlate with FGF-2 levels. Increased levels of FGF-2 with asthma severity were confirmed in bronchial biopsies by immunohistochemistry. CONCLUSIONS: Level of FGF-2 in induced sputum represents a relevant remodeling biomarker of asthma severity and significantly correlates with pulmonary function. FGF-2 sputum biomarker is proposed to reveal the phenotype of asthma characterized by fixed airflow obstruction.

IL-22 contributes to TGF-ß1-mediated epithelial-mesenchymal transition in asthmatic bronchial epithelial cells.

BACKGROUND: Allergic asthma is characterized by airway inflammation in response to antigen exposure, leading to airway remodeling and lung dysfunction. Epithelial-mesenchymal transition (EMT) may play a role in airway remodeling through the acquisition of a mesenchymal phenotype in airway epithelial cells. TGF-ß1 is known to promote EMT; however, other cytokines expressed in severe asthma with extensive remodeling, such as IL-22, may also contribute to this process. In this study, we evaluated the contribution of IL-22 to EMT in primary bronchial epithelial cells from healthy and asthmatic subjects. METHODS: Primary bronchial epithelial cells were isolated from healthy subjects, mild asthmatics and severe asthmatics (n=5 patients per group). The mRNA and protein expression of epithelial and mesenchymal cell markers and EMT-associated transcription factors was evaluated following stimulation with TGF-ß1, IL-22 and TGF-ß1+IL-22. RESULTS: Primary bronchial epithelial cells stimulated with TGF-ß1 underwent EMT, demonstrated by decreased expression of epithelial markers (E-cadherin and MUC5AC) and increased expression of mesenchymal markers (N-cadherin and vimentin) and EMT-associated transcription factors. IL-22 alone had no effect on epithelial or mesenchymal gene expression. However, IL-22+TGF-ß1 promoted the expression of some EMT transcription factors (Snail1 and Zeb1) and led to a more profound cadherin shift, but only in cells obtained from severe asthmatics. CONCLUSION: The impact of IL-22 on airway epithelial cells depends on the cytokine milieu and the clinical phenotype of the patient. Further studies are required to determine the molecular mechanism of IL-22 and TGF-ß1 cooperativity in driving EMT in primary human bronchial epithelial cells.

Airway remodeling and inflammation in competitive swimmers training in indoor chlorinated swimming pools.

BACKGROUND: Airway disorders are common in regular chlorinated swimming pool attendees, particularly competitive athletes, but the impact of intense swimming training on airway function and structure remains unclear. OBJECTIVE: This study aimed to evaluate airway inflammation and remodeling in elite swimmers. METHODS: Twenty-three elite swimmers were tested during off-training season. All had exhaled nitric oxide measurement, methacholine test, eucapnic voluntary hyperpnea challenge, allergy skin prick tests, and bronchoscopy with bronchial biopsies. Clinical data and tissues from 10 age-matched mild-asthmatic and 10 healthy nonallergic subjects were used for comparison. RESULTS: Swimmers had increased airway mucosa eosinophil and mast cell counts than did controls (P < .05). They had more goblet cell hyperplasia and higher mucin expression than did healthy or asthmatic subjects (P < .05). A greater submucosal type I and III collagen expression and tenascin deposition was also observed in swimmers than in controls (P < .05). Neither exhaled nitric oxide nor airway responsiveness to methacholine or eucapnic voluntary hyperpnea challenge correlated with these inflammatory and remodeling changes. CONCLUSION: Intense, long-term swimming training in indoor chlorinated swimming pools is associated with airway changes similar to those seen in mild asthma, but with higher mucin expression. These changes were independent from airway hyperresponsiveness. The long-term physiological and clinical consequences of these changes remain to be clarified.

Discrepancy in the suppressive function of regulatory T cells in allergic asthmatic vs. allergic rhinitis subjects upon low-dose allergen challenges.

Background: Regulatory T cells (Tregs) contribute to the maintenance of immunological tolerance. There is evidence of impaired function of these cells in people with asthma and allergy. In this study, we evaluated and compared the function of Tregs in allergic asthmatic and allergic non-asthmatic patients, both before and after low-dose allergen challenges. Methods: Three groups of subjects were recruited for a baseline evaluation: healthy controls without allergy or asthma, allergic asthmatic subjects, and allergic non-asthmatic subjects. All of them were subjected to expiratory flow measurements, sputum induction, and blood sampling. In addition, both groups of allergic subjects underwent low-dose allergen challenges. Tregs were isolated from whole blood using CD4+CD25high and CD127low staining. The suppression function was measured by flow cytometry. The levels of IL-10, IFN-γ, IgG4, IgA, and TGF-ß were measured using ELISA, and sputum Foxp3 was evaluated using qRT-PCR. Results: The suppressive function of Tregs in healthy controls was significantly higher than in allergic asthmatic or allergic non-asthmatic subjects. Repeated exposure to low doses of allergen increased the suppressor function of Tregs in allergic non-asthmatic subjects but decreased it in allergic asthmatic subjects. Foxp3 gene expression was increased in induced sputum in allergic non-asthmatic subjects, whereas it did not change in asthmatic subjects. Serum IL-10 level was decreased in allergic asthmatic subjects after allergen challenge but not in allergic non-asthmatic subjects. IFN-γ level increased upon allergen challenge in allergic non-asthmatic subjects. IgG4 level was higher in allergic non-asthmatic subjects than in allergic asthmatic subjects. Conclusions: Low-dose allergen challenges stimulate the suppressor function of Tregs in non-asthmatic allergic subjects but not in allergic asthmatic subjects.

Bronchial thermoplasty attenuates bronchodilator responsiveness.

INTRODUCTION: Bronchial thermoplasty is an effective intervention to improve respiratory symptoms and to reduce the rate of exacerbations in uncontrolled severe asthma. A reduction in airway smooth muscle is arguably the most widely discussed mechanisms accounting for these clinical benefits. Yet, this smooth muscle reduction should also translate into an impaired response to bronchodilator drugs. This study was designed to address this question. METHODS: Eight patients with clinical indication for thermoplasty were studied. They were uncontrolled severe asthmatics despite optimal environmental control, treatment of comorbidities, and the use of high-dose inhaled corticosteroids and long-acting ß2-agonists. Lung function measured by spirometry and respiratory mechanics measured by oscillometry were examined pre- and post-bronchodilator (salbutamol, 400 µg), both before and at least 1 year after thermoplasty. RESULTS: Consistent with previous studies, thermoplasty yielded no benefits in terms of baseline lung function and respiratory mechanics, despite improving symptoms based on two asthma questionnaires (ACQ-5 and ACT-5). The response to salbutamol was also not affected by thermoplasty based on spirometric readouts, including forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and FEV1/FVC ratio. However, a significant interaction was observed between thermoplasty and salbutamol for two oscillometric readouts, namely reactance at 5 Hz (Xrs5) and reactance area (Ax), showing an attenuated response to salbutamol after thermoplasty. CONCLUSIONS: Thermoplasty attenuates the response to a bronchodilator. We argue that this result is a physiological proof of therapeutic efficacy, consistent with the well-described effect of thermoplasty in reducing the amount of airway smooth muscle.

The reduction of airway smooth muscle by bronchial thermoplasty stands the test of time.

Airway smooth muscle ablation induced by thermoplasty is maintained for >10 years along with the improvements in asthma control https://bit.ly/3nGqQSP.

Thymic stromal lymphopoietin receptor-mediated IL-6 and CC/CXC chemokines expression in human airway smooth muscle cells: role of MAPKs (ERK1/2, p38, and JNK) and STAT3 pathways.

Thymic stromal lymphopoietin (TSLP) plays a pivotal role in allergic diseases such as asthma, chronic obstructive pulmonary disease, and atopic dermatitis. Enhanced TSLP expression has been detected in asthmatic airways that correlated with both the expression of Th2-attracting chemokines and with disease severity. Although cumulative evidence suggests that human airway smooth muscle (HASM) cells can initiate or perpetuate the airway inflammation by secreting a variety of inflammatory cell products such as cytokines and chemokines, the role of TSLP in this pathway is not known. In the current study, we sought to investigate whether HASM cells express the TSLP receptor (TSLPR) and whether it is functional. We first demonstrated that primary HASM cells express the transcript and protein of both TSLPR subunits (TSLPR and IL-7Ralpha). Functionally, TSLPR-mediated HASM activation induced a significant increase in CXC (IL-8/CXCL8), CC (eotaxin-1/CCL11) chemokines, and proinflammatory cytokine IL-6 expression. Furthermore, using biochemical and genetic approaches, we found that TSLP-induced proinflammatory gene expression in HASM involved the transcriptional mechanisms, MAPKs (ERK1/2, p38, and JNK), and STAT3 activation. Finally, TSLPR immunoreactivity in bronchial sections from mild allergic asthmatics suggested the potential in vivo TSLP targeting of HASM. Altogether, our data suggest that the TSLPR-mediated HASM activation induces proinflammatory cytokine and chemokines release that may facilitate inflammatory immune cells recruitment in airways. In addition, it may be inferred that TSLPR is involved in the pathogenesis of allergic asthma through the activation of HASM cells by TSLP.

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. CONCLUSION: 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.