PubMed Health⌕ Search

Biomedical subjects

David A Schwartz

Publications and source records attributed to David A Schwartz.

At least 19 recordsLinked to original sources
PubMed2025

Multi-ancestry genome-wide and transcriptome-wide association analyses identified new risk loci and genes for inflammatory bowel disease.

To advance genetic understanding of inflammatory bowel disease (IBD), we conducted genome-wide association meta-analyses of 63,415 IBD cases of European and East Asian descendants and identified 90 previously unknown risk loci. Integrating multi-ancestry transcriptome-wide association studies (TWAS), cell type-specific TWAS, alternative splicing (AS-WAS), and alternative polyadenylation (APA-WAS) analyses using RNA-seq data from normal colon tissues of 707 European and 364 East Asian individuals, we uncovered 506 high-confidence IBD risk genes, including 384 not previously reported. These genes converge on immune regulation, microbial interaction, and other pathways central to IBD pathogenesis, with over half showing transcriptional dysregulation supported by single-cell and spatial omics analyses. Notably, 46 risk genes are targeted by 225 drugs that have been approved or in Phase II/III trials, including sulfasalazine already used in IBD therapy. Our study findings deepen the understanding of IBD genetics and support the development of precision medicine for its prevention and treatment.

GWAS↗
PubMed2007

Using mouse genomics to understand idiopathic interstitial fibrosis.

Idiopathic interstitial pneumonia represents a broad category of lung disorders characterized by scarring or fibrosis of the lung accompanied by varying degrees of inflammation. A number of important hypotheses based on clinical observations have substantially contributed to our understanding of the pathogenesis of the most insidious and devastating of the idiopathic interstitial pneumonias, idiopathic interstitial fibrosis (IIF). Patients with IIF usually present late in the course of their illness; thus, animal models of the early, preclinical stage of these diseases are needed. Although no model faithfully recapitulates the clinical course of disease or the histopathology observed in humans, all result in scarring of the lung and may therefore be used to understand the biological processes that contribute to this scarring. The purpose of this article is to summarize the application of mouse genetic and genomic tools to these models to advance our understanding of IIF and to describe emerging agnostic approaches to identifying genes important to the fibroproliferative component of IIF.

Animals↗
PubMed2006

Complement levels and activity in the normal and LPS-injured lung.

Complement, a complex protein system, plays an essential role in host defense through bacterial lysis, stimulation of phagocytosis, recruitment of immune cells to infected tissue, and promotion of the inflammatory response. Although complement is most well-characterized in serum, complement activity is also present in the lung. Here we further characterize the complement system in the normal and inflamed lung. By Western blot, C5, C6, and factor I were detected in bronchoalveolar lavage (BAL) at lower levels than in serum, whereas C2 was detected at similar levels in BAL and serum. C4 binding protein (C4BP) was not detectable in BAL. Exposure to lipopolysaccharide (LPS) elevated levels of C1q, factor B, C2, C4, C5, C6, and C3 in human BAL and C3, C5, and factor B in mouse and rat BAL. Message for C1q-B, C1r, C1s, C2, C4, C3, C5, C6, factor B, and factor H, but not C9 or C4BP, was readily detectable by RT-PCR in normal mouse lung. Exposure to LPS enhanced factor B expression, decreased C5 expression, and did not affect C1q-B expression in mouse and rat lung. BAL from rats exposed to LPS had a greater ability to deposit C3b onto bacteria through complement activation than did BAL from control rats. In summary, these data demonstrate that complement levels, expression, and function are altered in acute lung injury and suggest that complement within the lung is regulated to promote opsonization of pathogens and limit potentially harmful inflammation.

Animals↗
PubMed2006

Cytokine gene polymorphisms are not associated with bronchiolitis obliterans syndrome or survival after lung transplant.

BACKGROUND: Cytokine polymorphisms are inconsistently associated with transplant rejection and other adverse outcomes. To address this controversy, we evaluated cytokine single nucleotide polymorphisms (SNPs) in a lung transplant cohort. METHODS: All patients who underwent lung transplantation from 1993 to 1998 and had post-transplant survival of at least 6 months were included in the initial analysis. Subjects were genotyped for: TNF-alpha -308 G/A; IFN-gamma +874 A/T; TGF-beta1 +869 T/C and +915 G/C; IL-10 -1082 A/G, -819 C/T and -592 C/A; and IL-6 -174 G/C. End-points were onset of broncholitis obliterans syndrome (BOS) and survival. RESULTS: In the cohort, 78 subjects, with an overall mean +/- SE survival 2,339 +/- 117 days, had no correlation between onset of BOS1, BOS2 or survival with TNF-alpha, IFN-gamma, TGF-beta1 or IL-10 gene polymorphisms. However, IL-6 polymorphisms GG or GC were associated with an earlier onset of BOS1 (p = 0.039), BOS2 (p = 0.021), and decreased overall post-transplant survival (p = 0.038). A second cohort of more recent lung transplant recipients did not validate an association between IL-6 polymorphisms and earlier onset of BOS1 (p = 0.70), BOS2 (p = 0.54) or overall post-transplant survival (p = 0.25). CONCLUSIONS: Polymorphisms of TNF-alpha, IFN-gamma, TGF-beta1, IL-10 and IL-6 do not appear to influence the onset of BOS or graft survival in recipients.

Adolescent↗
PubMed2006

Genetic basis of murine responses to hyperoxia-induced lung injury.

To evaluate the effect of genetic background on oxygen (O2) toxicity, nine genetically diverse mouse strains (129/SvIm, A/J, BALB/cJ, BTBR+(T)/tf/tf, CAST/Ei, C3H/HeJ, C57BL/6J, DBA/2J, and FVB/NJ) were exposed to more than 99% O2 for 72 h. Immediately following the hyperoxic challenge, the mouse strains demonstrated distinct pathophysiologic responses. The BALB/cJ and CAST/Ei strains, which were the only strains to demonstrate mortality from the hyperoxic challenges, were also the only strains to display significant neutrophil infiltration into their lower respiratory tract. In addition, the O2-challenged BALB/cJ and CAST/Ei mice were among six strains (A/J, BALB/cJ, CAST/Ei, BTBR+(T)/tf/tf, DBA/2J, and C3H/HeJ) that had significantly increased interleukin 6 concentrations in the whole lung lavage fluid and were among all but one strain that had large increases in lung permeability compared with air-exposed controls. In contrast, the DBA/2J strain was the only strain not to have any significant alterations in lung permeability following hyperoxic challenge. The expression of the extracellular matrix proteins, including collagens I, III, and IV, fibronectin I, and tenascin C, also varied markedly among the mouse strains, as did the activities of total superoxide dismutase (SOD) and manganese-SOD (Mn-SOD or SOD2). These data suggest that the response to O2 depends, in part, on the genetic background and that some of the strains analyzed can be used to identify specific loci and genes underlying the response to O2.

Animals↗
PubMed2006

Urine PGE-M: A metabolite of prostaglandin E2 as a potential biomarker of advanced colorectal neoplasia.

BACKGROUND & AIMS: The enzyme cyclooxygenase-2 is expressed in a majority of colorectal carcinomas (CRCs) and is important in prostaglandin production. We have developed an accurate method to measure the urinary metabolite of prostaglandin E(2) (PGE-M) using recently developed mass spectrometric techniques. The purpose of this pre-validation study was to determine if urinary PGE-M levels can be used as a biomarker to discriminate between healthy patients and those with colorectal disease. METHODS: Urine PGE-M was assessed in a total of 228 patients with CRC, colonic adenomatous polyps, Crohn's disease, and in subjects with no endoscopically detectable disease. Thirteen rectal carcinoma patients were treated with celecoxib and urinary PGE-M was measured before and after treatment. RESULTS: Urine PGE-M levels were increased among healthy men compared with healthy women (median, 8.59 [interquartile range (IQR), 5.67-22.3] vs 4.25 [IQR, 2.35-6.03], P = .0027). Urine PGE-M levels among patients with Crohn's disease (median, 19.85 [IQR, 6.89-90.2]), CRC (median, 14.65 [IQR, 5.94-92.1]), or large adenomas greater than 1 cm in size (median, 18.85 [IQR, 11.9-25.6]) were significantly increased when compared with patients who had either small polyps less than 1 cm in size (median, 9.69 [IQR, 6.41-22.2]), or no polyps (median, 7.05 [IQR, 2.35-24.7]) (P = .0001). PGE-M levels decreased significantly after celecoxib treatment in patients with rectal cancer (median, 21.7 [IQR, 16.2-29.9] vs 9.14 [IQR, 7.14-13.2], P = .009). CONCLUSIONS: The increase in urinary PGE-M in patients with colorectal cancers and large adenomas suggests that urinary PGE-M is a potentially useful biomarker for the detection of advanced colorectal neoplasia.

Adenoma↗
PubMed2006

Gene expression profiling of familial and sporadic interstitial pneumonia.

RATIONALE: Idiopathic interstitial pneumonia (IIP) and its familial variants are progressive and largely untreatable disorders with poorly understood molecular mechanisms. Both the genetics and the histologic type of IIP play a role in the etiology and pathogenesis of interstitial lung disease, but transcriptional signatures of these subtypes are unknown. OBJECTIVES: To evaluate gene expression in the lung tissue of patients with usual interstitial pneumonia or nonspecific interstitial pneumonia that was either familial or nonfamilial in origin, and to compare it with gene expression in normal lung parenchyma. METHODS: We profiled RNA from the lungs of 16 patients with sporadic IIP, 10 with familial IIP, and 9 normal control subjects on a whole human genome oligonucleotide microarray. RESULTS: Significant transcriptional differences exist in familial and sporadic IIPs. The genes distinguishing the genetic subtypes belong to the same functional categories as transcripts that distinguish IIP from normal samples. Relevant categories include chemokines and growth factors and their receptors, complement components, genes associated with cell proliferation and death, and genes in the Wnt pathway. The role of the chemokine CXCL12 in disease pathogenesis was confirmed in the murine bleomycin model of lung injury, with C57BL/6(CXCR4+/-) mice demonstrating significantly less collagen deposition than C57BL/6(CXCR4+/+) mice. Whereas substantial differences exist between familial and sporadic IIPs, we identified only minor gene expression changes between usual interstitial pneumonia and nonspecific interstitial pneumonia. CONCLUSIONS: Taken together, our findings indicate that differences in gene expression profiles between familial and sporadic IIPs may provide clues to the etiology and pathogenesis of IIP.

Adult↗
PubMed2006

Leukocyte-derived IL-10 reduces subepithelial fibrosis associated with chronically inhaled endotoxin.

Endotoxin (LPS), a Gram-negative cell wall component, has potent proinflammatory properties. Acute LPS exposure causes airway inflammation; chronic exposure causes airway hyperreactivity and remodeling. IL-10 is an important antiinflammatory cytokine, which is decreased in patients with airway disease, such as asthma and cystic fibrosis. To examine the physiologic and therapeutic role of IL-10 in acute and chronic LPS-induced airway disease. Mice were exposed to aerosolized LPS once or daily for 4 wk. Endpoints were airway inflammation, airway reactivity to methacholine, extracellular matrix protein expression, and histologic analysis. IL-10-deficient mice developed significantly enhanced airway cellularity and remodeling when compared with C57BL/6 mice after chronic LPS inhalation. However they demonstrated less airway hyperreactivity associated with higher inducible nitric oxide synthase (iNOS), endothelial NOS (eNOS), and lung lavage fluid nitrite levels. In a bone marrow transplantation model, the IL-10 antiinflammatory effect was dependent on the hematopoietic but not on the parenchymal IL-10 expression. Induced epithelial human IL-10 expression protected from the LPS effects and led to decreased collagen production. IL-10 attenuates chronic LPS-induced airway inflammation and remodeling. Physiologically, the antiinflammatory effect of IL-10 is mediated by hematopoietic cells. Therapeutically, adenovirus-driven expression of human IL-10 in airway epithelia is sufficient for its protective effect on inflammation and remodeling. The role of IL-10 on airway hyperreactivity is complex: IL-10 deficiency protects against LPS-induced hyperreactivity, and is associated with higher eNOS, iNOS, and airway nitrate levels.

Adenoviridae↗
PubMed2006

The transcriptional response to lipopolysaccharide reveals a role for interferon-gamma in lung neutrophil recruitment.

Neutrophil recruitment to the lung after lipopolysaccharide (LPS; endotoxin) inhalation is primarily dependent on Toll-like receptor 4 (Tlr4) signaling, because it is virtually absent in mice deficient in Tlr4. However, among strains wild type for Tlr4, the magnitude of neutrophil recruitment to the lung after LPS inhalation is variable, suggesting the involvement of genes other than Tlr4. To identify genes associated with the inflammatory response to inhaled LPS, we evaluated the transcriptional response in lungs of 12 inbred strains of mice, 8 which are wild type for Tlr4 and 4 of which lack functional Tlr4. Using the promoter integration in microarray analysis algorithm, we scanned our gene list for transcription factor-binding sites significantly overrepresented among Tlr4 wild-type strains with high neutrophil influx in the lung after LPS inhalation. This analysis identified the interferon (IFN)-stimulated response element (ISRE) as the most overrepresented transcription factor (present in 24% of the promoters) associated with the neutrophil influx to the lower respiratory tract. To test the validity of this observation, we evaluated IFN-gamma-deficient mice and found that the presence of IFN-gamma is essential for robust neutrophil recruitment to the lower respiratory tract and modulation of key regulatory cytokines and chemokines after LPS inhalation. In conclusion, using a genomic approach, we identified the ISRE as a transcriptional element associated with the neutrophil response to inhaled LPS and demonstrated for the first time that IFN-gamma plays a critical role in LPS-induced neutrophil recruitment to the lower airways.

Administration, Inhalation↗
PubMed2006

TLR4 signaling attenuates ongoing allergic inflammation.

The relationship between LPS exposure and allergic asthma is poorly understood. Epidemiologic studies in humans have found that exposure to LPS can protect, have no effect, or exacerbate allergic asthma. Similarly, LPS has had variable effects on allergic pulmonary inflammation in the mouse, depending on the model used. In the present study, we studied the effect of very low doses of LPS in models of both short-term and long-term allergen challenge. When challenged with allergen for short periods, wild-type and tlr4-deficient mice had similar responses. However, when challenged for periods of 1 wk or longer, tlr4-deficient mice developed dramatically increased airway eosinophils, serum IgE, and Th2 cytokines compared with similarly challenged, genetically matched C57BL/6 mice. The relative attenuation of allergic responses seen in C57BL/6 mice was dependent on bone marrow-derived cell-specific expression of tlr4, and was not associated with an increase in Th1 responses. The number of dendritic cells in lungs of challenged tlr4-deficient mice was significantly increased compared with those in challenged C57BL/6 mice. No differences were seen in the abilities of naive C57BL/6 and tlr4-deficient mice to develop allergen-specific tolerance after exposure to similar preparations of OVA, suggesting that tolerance and regulation of existing inflammation develop through different mechanisms. The attenuation of eosinophilic inflammation in C57BL/6 mice was abolished when these mice were challenged with OVA supplemented with additional LPS. Together, these findings show that low doses of endotoxin can have regulatory effects on allergic inflammation, particularly in the setting of ongoing allergen exposure.

Allergens↗
PubMed2006

Multistrain genetic comparisons reveal CCR5 as a receptor involved in airway hyperresponsiveness.

Asthma is a ubiquitous disease with a broad range of clinical phenotypes. To better understand the complex genetic and environmental interactions underlying asthma, we compared the gene-gene interactions of four genetically distinct mouse strains that demonstrate biologically distinct responses to allergen. Using DNA microarrays and knock-out mouse studies, we showed that CCR5 plays a definitive role in the development of ovalbumin-induced allergic airway inflammatory disease. In addition, gene expression profiling data have revealed other potential novel targets for therapeutics-based research and has enhanced the understanding of the molecular mechanisms underlying the etiology of "asthma."

Animals↗
PubMed2006

Routine vs. selective EUS-guided FNA approach for preoperative nodal staging of esophageal carcinoma.

BACKGROUND: EUS-guided FNA (EUS-FNA) is the most accurate method for lymph-node staging of esophageal carcinoma; however, it may not be necessary when EUS features are present that strongly suggest a benign or a malignant origin. AIMS: (1) To identify a combination of EUS criteria that have a sufficient sensitivity and specificity to preclude the need for EUS-FNA and (2) to assess the cost savings derived from a selective EUS-FNA approach. METHODS: A total of 144 patients with esophageal carcinoma were prospectively evaluated with EUS. Accuracy of standard (hypoechoic, smooth border, round, or width > 5 mm) and modified (4 standard plus EUS identified celiac lymph nodes, >5 lymph nodes, or EUS T3/4 tumor) criteria were compared (receiver operating characteristic curves). Resource utilization of two diagnostic strategies, routine (all patients with lymph nodes) and selective EUS-FNA (FNA only in those patients in whom the number of EUS malignant criteria provides a sensitivity and a specificity <100%), were compared. RESULTS: Modified EUS criteria for lymph-node staging were more accurate than standard criteria (area under the curve 0.88 vs. 0.78, respectively). No criterion alone was predictive of malignancy; sensitivity and specificity reached 100% when a cutoff value of >1 and >6 modified criteria were used, respectively. The EUS-FNA selective approach may avoid performing FNA in 61 patients (42%). CONCLUSIONS: Modified EUS lymph-node criteria are more accurate than standard criteria. A selective EUS-FNA approach reduced the cost by avoiding EUS-FNA in 42% of patients with esophageal carcinoma. These results require confirmation in future studies.

Adult↗