Claire Doerschuk
University of North Carolina at Chapel Hill, Medicine, Faculty Member
Cobra venom factor (CVF) induces lung injury through oxidant- and neutrophil-dependent mechanisms. Adhesion molecules, particularly L-selectin, P-selectin, CD11/CD18, and ICAM-1, are required for full expression of injury in rats. This... more
Cobra venom factor (CVF) induces lung injury through oxidant- and neutrophil-dependent mechanisms. Adhesion molecules, particularly L-selectin, P-selectin, CD11/CD18, and ICAM-1, are required for full expression of injury in rats. This study compared the roles of P-selectin and ICAM-1 using either mutant mice or blocking Abs. Mice deficient in either P-selectin, ICAM-1, or both adhesion molecules were compared with wild-type mice. Wild-type and single mutant mice were given Abs against murine P-selectin or ICAM-1. CVF was injected i.v., and neutrophil sequestration and extravascular albumin were measured 30 min later. Neither P-selectin, ICAM-1, nor P-selectin/ICAM-1 double mutants showed a reduction in neutrophil sequestration or lung injury when compared with wild-type mice. Anti-P-selectin Abs inhibited both sequestration and injury in wild-type mice by 57% and 60%, respectively, but had no effect in P-selectin mutants. Similar results were found using anti-ICAM-1 Ab in wild-type...
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Neutrophil accumulation in response to Pseudomonas aeruginosa in the lungs is mediated through CD11/CD18. This study determined the roles of CD11a, CD11b, and intercellular adhesion molecule (ICAM)-1 in P. aeruginosa-induced pneumonia and... more
Neutrophil accumulation in response to Pseudomonas aeruginosa in the lungs is mediated through CD11/CD18. This study determined the roles of CD11a, CD11b, and intercellular adhesion molecule (ICAM)-1 in P. aeruginosa-induced pneumonia and compared the function of ICAM-1 using Abs or ICAM-1 mutant mice. Anesthetized BALB/c mice pretreated with either Abs against CD11a, CD11b, ICAM-1, or rat IgG received intratracheal instillation of P. aeruginosa for 4 h. In other studies, ICAM-1 mutant and wild-type mice received either anti-ICAM-1 Ab or rat IgG followed by instillation of P. aeruginosa. The data show that Abs against CD11a, CD11b, and ICAM-1 in BALB/c mice inhibited neutrophil emigration by 79, 81, and 56%, respectively. ICAM-1 mutant mice showed no inhibition of neutrophil emigration compared with wild-type mice. Pretreatment with anti-ICAM-1 Ab inhibited neutrophil emigration in wild-type (129/SvxC57) mice by 67% but had no effect in ICAM-1 mutant mice, suggesting that the Ab was...
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Pneumonia is a complex pulmonary disease in need of new clinical approaches. Although triggered by a pathogen, pneumonia often results from dysregulations of host defense that likely precede infection. The coordinated activities of immune... more
Pneumonia is a complex pulmonary disease in need of new clinical approaches. Although triggered by a pathogen, pneumonia often results from dysregulations of host defense that likely precede infection. The coordinated activities of immune resistance and tissue resilience then dictate whether and how pneumonia progresses or resolves. Inadequate or inappropriate host responses lead to more severe outcomes such as acute respiratory distress syndrome and to organ dysfunction beyond the lungs and over extended time frames after pathogen clearance, some of which increase the risk for subsequent pneumonia. Improved understanding of such host responses will guide the development of novel approaches for preventing and curing pneumonia and for mitigating the subsequent pulmonary and extrapulmonary complications of pneumonia. The NHLBI assembled a working group of extramural investigators to prioritize avenues of host-directed pneumonia research that should yield novel approaches for interrupt...
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Pneumonia is a complex pulmonary disease in need of new clinical approaches. While triggered by a pathogen, pneumonia often results from dysregulations of host defense that likely precede infection. The coordinated activities of immune... more
Pneumonia is a complex pulmonary disease in need of new clinical approaches. While triggered by a pathogen, pneumonia often results from dysregulations of host defense that likely precede infection. The coordinated activities of immune resistance and tissue resilience then dictate whether and how pneumonia progresses or resolves. Inadequate or inappropriate host responses lead to more severe outcomes such as ARDS and to organ dysfunction beyond the lungs and overextended time-frames after pathogen clearance, some of which increase the risk for subsequent pneumonias. Improved understanding of such host responses will guide the development of novel approaches for preventing and curing pneumonia and for mitigating the subsequent pulmonary and extra-pulmonary complications from pneumonia. The NHLBI assembled a Working Group of extramural investigators to prioritize avenues of host-directed pneumonia research that should yield novel approaches for interrupting the cycle of unhealthy decl...
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In the systemic circulation, neutrophil emigration into sites of acute inflammation is mediated through the leukocyte adhesion complex, CD11/CD18. ICAM-1 is an inducible endothelial ligand for CD11a/CD18 and CD11b/CD18. Streptococcus... more
In the systemic circulation, neutrophil emigration into sites of acute inflammation is mediated through the leukocyte adhesion complex, CD11/CD18. ICAM-1 is an inducible endothelial ligand for CD11a/CD18 and CD11b/CD18. Streptococcus pneumoniae elicits neutrophil emigration through a CD18-independent mechanism whereas Escherichia coli endotoxin elicits emigration through a CD18-dependent mechanism in rabbit lungs. To determine whether ICAM-1 is up-modulated in the lung during CD18-independent and CD18-dependent emigration, ultrastructural immunogold-labeling studies were performed on BALB/c mice given airway instillates of S. pneumoniae or E. coli endotoxin. Ultrathin cryosections of frozen lung tissue were immunogold labeled with the mAb YN1/1.7.4 against the murine homologue of human ICAM-1. Gold particles on the plasma membranes of alveolar endothelial and epithelial cells were quantitated by transmission electron microscopy. Capillary endothelial ICAM-1 expression did not change...
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Research Interests: Immunology, Biology, Medicine, Cell Division, Humans, and 15 moreMice, Animals, Male, Acute Lung Injury, Fibroblast Growth Factor, Lung, Lipopolysaccharides, Alveolar epithelial cells, Gene Expression Regulation, Diphtheria Toxin, Cell Growth, Adoptive Transfer, coculture techniques, Cardiovascular medicine and haematology, and Pneumonectomy
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In the systemic circulation, the leukocyte adhesion molecule, L-selectin facilitates the initial adhesion of the neutrophil to the inflamed endothelium, whereas CD11/CD18 is essential to transendothelial migration. Previous work from our... more
In the systemic circulation, the leukocyte adhesion molecule, L-selectin facilitates the initial adhesion of the neutrophil to the inflamed endothelium, whereas CD11/CD18 is essential to transendothelial migration. Previous work from our laboratory showed that neutrophil emigration in the lung occurs through either a CD18-independent or CD18-dependent mechanism, depending on the inflammatory stimulus. This study quantitated and compared the surface expression of L-selectin and CD18 on neutrophils in the lungs of rabbits during emigration toward Streptococcus pneumoniae (a CD18-independent stimulus) and Escherichia coli endotoxin (a CD18-dependent stimulus). Ultrathin frozen lung tissue sections were immunogold labeled for 1-selectin and CD18, and gold particles were quantitated on intravascular, interstitial, and airspace neutrophils by transmission electron microscopy. The results show that CD18-independent neutrophil emigration was associated with L-selectin down-modulation (78%) ...
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Neutrophil functions and responses are heterogeneous, and the nature and categorization of this heterogeneity is achieving considerable interest. Work by Li et al. in this issue of JEM (2021. J. Exp.... more
Neutrophil functions and responses are heterogeneous, and the nature and categorization of this heterogeneity is achieving considerable interest. Work by Li et al. in this issue of JEM (2021. J. Exp. Med.https://doi.org/10.1084/jem.20211083) identifies how a transcriptional repressor, DREAM, regulates adhesion of neutrophils to endothelial cells and their transmigration into tissue. This study offers a mechanism for heterogeneity in this critical response of neutrophils to inflammatory stimuli.
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New and emerging tobacco products pose a unique threat to pulmonary health. Little cigars are a class of tobacco which differ from cigarettes in that they are wrapped in any substance containing tobacco. We set out to examine the... more
New and emerging tobacco products pose a unique threat to pulmonary health. Little cigars are a class of tobacco which differ from cigarettes in that they are wrapped in any substance containing tobacco. We set out to examine the composition and relative effects of little cigars compared to Kentucky research cigarettes, emphasizing effects on the innate defense system of the lung. The chemical profile of tar particles from these products were also analyzed to see if they differed from cigarettes. Human bronchial epithelial cultures (HBECs) grown at the air liquid interface were exposed to air and whole tobacco smoke from Kentucky cigarettes, two leading brands of little cigars (Swisher Sweets and Captain Black), and one similar brand of cigar (Cheyenne) chronically for five days. These cells were then analyzed by western blot and confocal microscopy. We also exposed C57/BL6 mice to smoke from Kentucky cigarettes and Swisher Sweets little cigars. Broncho-alveolar lavage samples were ...
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Accurate and reliable measurements of exposure to tobacco products are essential for identifying and confirming patterns of tobacco product use and for assessing their potential biological effects in both human populations and... more
Accurate and reliable measurements of exposure to tobacco products are essential for identifying and confirming patterns of tobacco product use and for assessing their potential biological effects in both human populations and experimental systems. Due to the introduction of new tobacco-derived products and the development of novel ways to modify and use conventional tobacco products, precise and specific assessments of exposure to tobacco are now more important than ever. Biomarkers that were developed and validated to measure exposure to cigarettes are being evaluated to assess their utility for measuring exposure to these new products. Here, we review current methods for measuring exposure to new and emerging tobacco products, such as electronic cigarettes, little cigars, water pipe and cigarillos. Rigorously validated biomarkers specific to these new products are yet to be identified. Here, we discuss the strengths and limitations of current approaches, including whether or not ...
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Observational studies relating 25-hydroxyvitamin D (25(OH)D) and pregnancy outcomes have reported conflicting results. The aim was to assess maternal 25(OH)D status and its association with pregnancy outcomes. A prospective observational... more
Observational studies relating 25-hydroxyvitamin D (25(OH)D) and pregnancy outcomes have reported conflicting results. The aim was to assess maternal 25(OH)D status and its association with pregnancy outcomes. A prospective observational study was carried out in Guangzhou city (23 ºN), China. Pregnant women (n=2960) and healthy controls (n=100) were recruited at a teaching hospital. Maternal 25(OH)D levels were measured at 16-20-week gestation. The pregnant women, if met inclusion and exclusion criteria, were enrolled in further analysis for pregnancy outcomes (n=1953). Mean serum 25(OH)D in pregnant women was 27.03±7.92 ng/ml. In total, 18.9 and 48.6% of pregnant women had low (25(OH)D less than or equal to 20 ng/ml) and medium level (25(OH)D 21-29 ng/ml) of vitamin D, respectively. 25(OH)D was highest in summer and lowest in winter, which showed a positive correlation with temperature (R=0.942) and calcium (R=0.074). Most maternal outcomes (premature rupture of membranes break, po...
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To determine the role of CD11/CD18 complexes in neutrophil emigration, inflammation was induced in the skin, lungs, or peritoneum of mutant mice deficient in CD18 (CD18−/− mutants). Peripheral blood of CD18−/− mutants contained 11-fold... more
To determine the role of CD11/CD18 complexes in neutrophil emigration, inflammation was induced in the skin, lungs, or peritoneum of mutant mice deficient in CD18 (CD18−/− mutants). Peripheral blood of CD18−/− mutants contained 11-fold more neutrophils than did blood of wild-type (WT) mice. During irritant dermatitis induced by topical application of croton oil, the number of emigrated neutrophils in histological sections of dermis was 98% less in CD18−/− mutants than in WT mice. During Streptococcus pneumoniae pneumonia, neutrophil emigration in CD18−/− mutants was not reduced. These data are consistent with expectations based on studies using blocking antibodies to inhibit CD11/CD18 complexes, and on observations of humans lacking CD11/CD18 complexes. The number of emigrated neutrophils in lung sections during Escherichia coli pneumonia, or in peritoneal lavage fluid after 4 h of S. pneumoniae peritonitis, was not reduced in CD18−/− mutants, but rather was greater than the WT valu...
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Research Interests: Endothelial Cells, Mutation, Mice, Female, Animals, and 13 morePneumonia, Monoclonal Antibodies, Neutrophils, Edema, Antisense Oligonucleotide Drugs, Monoclonal Antibody, Base Sequence, Lung Injury, Adhesion molecules, Clinical Investigation, Endotoxins, Molecular Sequence Data, and Medical and Health Sciences
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Background —Heme oxygenase (HO)-1 is an enzyme that degrades heme to generate CO (a vasodilatory gas), iron, and the potent antioxidant bilirubin. A disease process characterized by decreases in vascular tone and increases in oxidative... more
Background —Heme oxygenase (HO)-1 is an enzyme that degrades heme to generate CO (a vasodilatory gas), iron, and the potent antioxidant bilirubin. A disease process characterized by decreases in vascular tone and increases in oxidative stress is endotoxic shock. Moreover, HO-1 is markedly induced in multiple organs after the administration of endotoxin (lipopolysaccharide [LPS]) to mice. Methods and Results —To determine the role of HO-1 in endotoxemia, we administered LPS to mice that were wild-type (+/+), heterozygous (±), or homozygous null (−/−) for targeted disruption of HO-1. LPS produced a similar induction of HO-1 mRNA and protein in HO-1 +/+ and HO-1 +/− mice, whereas HO-1 − /− mice showed no HO-1 expression. Four hours after LPS, systolic blood pressure (SBP) decreased in all the groups. However, SBP was significantly higher in HO-1 − /− mice (121±5 mm Hg) after 24 hours, compared with HO-1 +/+ (96±7 mm Hg) and HO-1 +/− (89±13 mm Hg) mice. A sustained increase in endotheli...
Research Interests: Membrane Proteins, Oxidative Stress, Mortality, Lipopolysaccharide, Mice, and 15 moreFemale, Animals, Iron, Heme Oxygenase, Lung, Enzyme, Clinical Sciences, Lipopolysaccharides, ENDOTOXEMIA, Public health systems and services research, Circulation, Hypotension, Multiple Organ Failure, Renal Dysfunction, and Cardiovascular medicine and haematology
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Although airway mucus dehydration is key to pathophysiology of cystic fibrosis (CF) and other airways diseases, measuring mucus hydration is challenging. We explored a robust method to estimate mucus hydration using sialic acid as a... more
Although airway mucus dehydration is key to pathophysiology of cystic fibrosis (CF) and other airways diseases, measuring mucus hydration is challenging. We explored a robust method to estimate mucus hydration using sialic acid as a marker for mucin content. Terminal sialic acid residues from mucins were cleaved by acid hydrolysis from airway samples, and concentrations of sialic acid, urea, and other biomarkers analyzed using mass spectrometry. In mucins purified from human airway epithelial (HAE), sialic acid concentrations after acid hydrolysis correlated with mucin concentrations (r2=0.92). Sialic acid/urea ratios measured from filters applied to the apical surface of cultured HAE correlated to % solids and were elevated in samples from CF HAEs relative to controls (2.2±1.1 vs. 0.93±1.8, p<0.01). Sialic acid/urea ratios were elevated in bronchoalveolar lavage fluid (BALF) from βENaC transgenic mice, known to have reduced mucus hydration, and mice sensitized to house dust mite allergen. In a translational application, elevated sialic acid/urea ratios were measured in BALF from young children with CF who had airway infection relative to those who did not (5.5±3.7 vs.1.9±1.4, p<0.02), and could be assessed simultaneously with established biomarkers of inflammation. The sialic acid/urea ratio performed similarly to % solids, the gold standard measure of mucus hydration. The method proved robust and has potential to serve as flexible techniques to assess mucin hydration, particularly in samples like BALF in which established methods such as % solids cannot be utilized.
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1. Am J Respir Cell Mol Biol. 2000 Aug;23(2):133-6. CD11/CD18-dependent and -independent neutrophil emigration in the lungs: how do neutrophils know which route to take? Doerschuk CM, Tasaka S, Wang Q. Division of ...
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Nrf2 regulates the transcriptional response to oxidative stress. These studies tested the role of Nrf2 during Streptococcus pneumoniae pneumonia and identified Nrf2-dependent genes and pathways in lung tissue and in recruited neutrophils.... more
Nrf2 regulates the transcriptional response to oxidative stress. These studies tested the role of Nrf2 during Streptococcus pneumoniae pneumonia and identified Nrf2-dependent genes and pathways in lung tissue and in recruited neutrophils. Nrf2 null and wild type (WT) mice were studied at 6 and 24 h after instillation of S. pneumoniae or PBS. At 6 h, fewer neutrophils were recruited and the number of bacteria remaining in the lungs tended to be less (p = 0.06) in the Nrf2 null compared with WT mice. In uninfected lungs, 53 genes were already differentially expressed in Nrf2 null compared with WT mouse lungs, and gene sets involved in phagocytosis, Fc receptor function, complement, and Ig regulation are enhanced in PBS-treated Nrf2 null gene profiles compared with those of WT mice. These results suggest that initial host defense is enhanced in Nrf2 null mice, resulting in less recruitment of neutrophils. At 24 h, neutrophil recruitment was greater. The percentages of early apoptotic a...
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Implementing precision medicine for complex diseases such as chronic obstructive lung disease (COPD) will require extensive use of biomarkers and an in-depth understanding of how genetic, epigenetic, and environmental variations... more
Implementing precision medicine for complex diseases such as chronic obstructive lung disease (COPD) will require extensive use of biomarkers and an in-depth understanding of how genetic, epigenetic, and environmental variations contribute to phenotypic diversity and disease progression. A meta-analysis from two large cohorts of current and former smokers with and without COPD [SPIROMICS (N = 750); COPDGene (N = 590)] was used to identify single nucleotide polymorphisms (SNPs) associated with measurement of 88 blood proteins (protein quantitative trait loci; pQTLs). PQTLs consistently replicated between the two cohorts. Features of pQTLs were compared to previously reported expression QTLs (eQTLs). Inference of causal relations of pQTL genotypes, biomarker measurements, and four clinical COPD phenotypes (airflow obstruction, emphysema, exacerbation history, and chronic bronchitis) were explored using conditional independence tests. We identified 527 highly significant (p < 8 X 10...
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Asthmatic airways are infiltrated with inflammatory cells that release mediators and cytokines into the microenvironment. In this study, we evaluated the distribution of CD45-positive leukocytes and eosinophils in lung tissue from five... more
Asthmatic airways are infiltrated with inflammatory cells that release mediators and cytokines into the microenvironment. In this study, we evaluated the distribution of CD45-positive leukocytes and eosinophils in lung tissue from five patients who died with severe asthma compared ...