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Secreted phospholipase A 2 s (sPLA 2 s) regulate eicosanoid formation and have been implicated in asthma. Although sPLA 2 s function as enzymes, some of the sPLA 2 s bind with high affinity to a C-type lectin receptor, called PLA2R1, which has functions in both cellular signaling and clearance of sPLA 2 s. We sought to examine the expression of PLA2R1 in the airway epithelium of human subjects with asthma and the function of the murine Pla2r1 gene in a model of asthma. Expression of PLA2R1 in epithelial brushings was assessed in two distinct cohorts of children with asthma by microarray and quantitative PCR, and immunostaining for PLA2R1 was conducted on endobronchial tissue and epithelial brushings from adults with asthma. C57BL/129 mice deficient in Pla2r1 (Pla2r1 2/2 ) were characterized in an ovalbumin (OVA) model of allergic asthma. PLA2R1 was differentially overexpressed in epithelial brushings of children with atopic asthma in both cohorts. Immunostaining for PLA2R1 in endobronchial tissue localized to submucosal glandular epithelium and columnar epithelial cells. After OVA sensitization and challenge, Pla2r1 2/2 mice had increased airway hyperresponsiveness, as well as an increase in cellular trafficking of eosinophils to the peribronchial space and bronchoalveolar lavage fluid, and an increase in airway permeability. In addition, Pla2r1 2/2 mice had more dendritic cells in the lung, higher levels of OVAspecific IgG, and increased production of both type-1 and type-2 cytokines by lung leukocytes. PLA2R1 is increased in the airway epithelium in asthma, and serves as a regulator of airway hyperresponsiveness, airway permeability, antigen sensitization, and airway inflammation.

No abstract

Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane regulator (CFTR) gene: the gene product responsible for transporting chloride and bicarbonate ions through the apical membrane of most epithelial cells. Major clinical features of CF include respiratory failure, pancreatic exocrine insufficiency, and intestinal disease. Many CF animal models have been generated, but some models fail to fully capture the phenotypic manifestations of human CF disease. Other models that better capture the key characteristics of the human CF phenotype are cost prohibitive or require special care to maintain. Important differences have been reported between the pathophysiology seen in human CF patients and in animal models. These limitations present significant limitations to translational research. This review outlines the study of CF using patient-derived organs-on-a-chip to overcome some of these limitations. Recently developed microfluidic-based organs-on-a-chip provide a human experimental model that allows researchers to manipulate environmental factors and mimic in vivo conditions. These chips may be scaled to support pharmaceutical studies and may also be used to study organ systems and human disease. The use of these chips in CF discovery science enables researchers to avoid the barriers inherent in animal models and promote the advancement of personalized medicine.

The online version of this article contains supplemental material. Abbreviations used in this article: AA, arachidonic acid; AHR, airway hyperresponsiveness; BAL, bronchoalveolar lavage; bvPLA 2 , bee venom PLA 2 ; bvPLA 2 /OVA, bvPLA 2 plus OVA; bvPLA 2 /Sal, bvPLA 2 alone; CysLT, cysteinyl leukotriene; DC, dendritic cell; FFA, free fatty acid; HDM, house dust mite; ILC2, type 2 innate lymphoid cell; LysoPL, lysophospholipid; MHCII, MHC class II; PMN, polymorphonuclear neutrophil; Sal/OVA, saline plus OVA; sPLA 2 , secreted phospholipase A 2 ; sPLA 2 -III, mammalian group III sPLA 2 ; sPLA 2 -X, sPLA 2 group X; WT, wild-type.

Cystic fibrosis is a deadly multi-organ disorder caused by loss of function mutations in the gene that encodes for the cystic fibrosis transmembrane conductance regulator (CFTR) chloride/bicarbonate ion channel. More than 1700 CFTR genetic variants exist that can cause CF, and, majority of these are extremely rare. Due to genetic and environmental influences, CF patients exhibit large phenotypic variation. These factors make clinical trials difficult and largely impractical due to limited and heterogenous patient pools. Also, the benefit of approved small-molecule CF modulators in a large number of rare mutation patients remain unknown. The goal of this study is to perform a comprehensive bench-side study using in vitro patient enteroids and in vivo mice implanted Human Intestinal Organoids (HIOs) to test CF modulator-Ivacaftor response for a rare CF mutation patient. Based on the positive Ivacaftor response in the enteroids, the patient was enrolled in N=1 clinical trial and showed improved clinical outcomes upon Ivacaftor treatment. HIO implantation model allowed in vivo modulator dosing and provided an elegant human organ-based demonstration of bench-to-bedside testing of modulator effects. Additionally, using the CF HIO model the role of CFTR function in the maturation of human intestine was reported for the first time. In all, we demonstrate that these models effectively serve to translate data from the lab to the clinic and back so that patient specific therapies could be easily identified and disease-relevant developmental abnormalities in CF organs could be studied and addressed.

Background: Patients with atopic dermatitis have an increased incidence of allergic asthma suggesting that dermal sensitization is an initial step in developing airway inflammation. However, the molecular mechanisms responsible for driving and regulating this "atopic march" remain unclear. We have previously found that secreted phospholipase A 2 group X (sPLA 2 -