IU Indianapolis ScholarWorks :: Browsing by Subject "Lung"

Browsing by Subject "Lung"

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Blimp-1 is essential for allergen-induced asthma and Th2 cell development in the lung
(Rockefeller University Press, 2020-07-06) He, Kun; Hettinga, Angela; Kale, Sagar Laxman; Hu, Sanmei; Xie, Markus M.; Dent, Alexander L.; Ray, Anuradha; Poholek, Amanda C.; Microbiology and Immunology, School of Medicine
A Th2 immune response is central to allergic airway inflammation, which afflicts millions worldwide. However, the mechanisms that augment GATA3 expression in an antigen-primed developing Th2 cell are not well understood. Here, we describe an unexpected role for Blimp-1, a transcriptional repressor that constrains autoimmunity, as an upstream promoter of GATA3 expression that is critical for Th2 cell development in the lung to inhaled but not systemically delivered allergens but is dispensable for TFH function and IgE production. Mechanistically, Blimp-1 acts through Bcl6, leading to increased GATA3 expression in lung Th2 cells. Surprisingly, the anti-inflammatory cytokine IL-10, but not the pro-inflammatory cytokines IL-6 or IL-21, is required via STAT3 activation to up-regulate Blimp-1 and promote Th2 cell development. These data reveal a hitherto unappreciated role for an IL-10-STAT3-Blimp-1 circuit as an initiator of an inflammatory Th2 response in the lung to allergens. Thus, Blimp-1 in a context-dependent fashion can drive inflammation by promoting rather than terminating effector T cell responses.
Deletion of airway cilia results in noninflammatory bronchiectasis and hyperreactive airways
(American Physiological Society (APS), 2014-01-15) Gilley, Sandra K.; Stenbit, Antine E.; Pasek, Raymond C.; Sas, Kelli M.; Steele, Stacy L.; Amria, May; Bunni, Marlene A.; Estell, Kimberly P.; Schwiebert, Lisa M.; Flume, Patrick; Gooz, Monika; Haycraft, Courtney J.; Yoder, Bradley K.; Miller, Caroline; Pavlik, Jacqueline A.; Turner, Grant A.; Sisson, Joseph H.; Bell, P. Darwin; Department of Anatomy & Cell Biology, IU School of Medicine
The mechanisms for the development of bronchiectasis and airway hyperreactivity have not been fully elucidated. Although genetic, acquired diseases and environmental influences may play a role, it is also possible that motile cilia can influence this disease process. We hypothesized that deletion of a key intraflagellar transport molecule, IFT88, in mature mice causes loss of cilia, resulting in airway remodeling. Airway cilia were deleted by knockout of IFT88, and airway remodeling and pulmonary function were evaluated. In IFT88− mice there was a substantial loss of airway cilia on respiratory epithelium. Three months after the deletion of cilia, there was clear evidence for bronchial remodeling that was not associated with inflammation or apparent defects in mucus clearance. There was evidence for airway epithelial cell hypertrophy and hyperplasia. IFT88− mice exhibited increased airway reactivity to a methacholine challenge and decreased ciliary beat frequency in the few remaining cells that possessed cilia. With deletion of respiratory cilia there was a marked increase in the number of club cells as seen by scanning electron microscopy. We suggest that airway remodeling may be exacerbated by the presence of club cells, since these cells are involved in airway repair. Club cells may be prevented from differentiating into respiratory epithelial cells because of a lack of IFT88 protein that is necessary to form a single nonmotile cilium. This monocilium is a prerequisite for these progenitor cells to transition into respiratory epithelial cells. In conclusion, motile cilia may play an important role in controlling airway structure and function.
Differential effect of mild and severe pulmonary embolism on the rat lung transcriptome
(Springer (Biomed Central Ltd.), 2016-07-19) Zagorski, John; Kline, Jeffrey A.; Department of Emergency Medicine, IU School of Medicine
BACKGROUND: Pulmonary thromboembolism (PTE) is a common diagnosis and a leading cause of cardiovascular morbidity and mortality. A growing literature has associated PE with systemic inflammation, and global hyper-coagulability, which contribute to lung remodeling and clot recurrence. The source and mechanism of inflammation remains unstudied. In humans, inhibition of cholesterol synthesis with statins decreases biomarkers of inflammation. We test the differential effect of pulmonary vascular occlusion during mild and severe pulmonary embolism on the lung transcriptome. METHODS: Experimental PE was induced in adult male rats by injection of 25 micron polystyrene microspheres into the jugular vein. The effect of Mild PE, (2-h right ventricular systolic pressure [RVSP] normal, 18-h RVSP 44 mmHg) and Severe PE (2-h RVSP > 50 mmHg; 18-h RVSP 44 mmHg) on lungs was assessed by measuring transcriptome-wide changes in gene expression by DNA microarrays. RESULTS: Severe PE was associated with a large change in lung gene expression and in the expression of KEGG pathways and other gene functional annotation groups. Mild PE was also associated with a large number of significant changes in gene expression and in the expression of KEGG pathways and gene functional annotation groups, even after only 2 h of PE. Up-regulated pathways included increased adipocytokine, chemokine and cytokine signaling as well as cholesterol synthesis. CONCLUSIONS: Mild PE without acute pulmonary hypertension (PH) increased lung gene expression of inflammatory pathways, including increased cholesterol synthesis. These data indicate that even mild persistent pulmonary vascular occlusion is capable of inciting an inflammatory response from the lung. These data imply the detrimental effect of unresolved pulmonary obstruction from PE.
The effect of hypoxia on ER-β expression in the lung and cultured pulmonary artery endothelial cells
(2014-03-12) Selej, Mona M.A.; Lahm, Tim; Petrache, Irina; Schweitzer, Kelly S.
17-β estradiol (E2) exerts protective effects in hypoxia-induced pulmonary hypertension (HPH) via endothelial cell estrogen receptor (ER)-dependent mechanisms. However, the effects of hypoxia on ER expression in the pulmonary-right ventricle (RV) axis remain unknown. Based on previous data suggesting a role of ER-β in mediating E2 protection, we hypothesized that hypoxia selectively up-regulates ER-β in the lung and pulmonary endothelial cells. In our Male Sprague-Dawley rat model, chronic hypoxia exposure (10% FiO2) resulted in a robust HPH phenotype associated with significant increases in ER- β but not ER-α protein in the lung via western blotting. More importantly, this hypoxia-induced ER-β increase was not replicated in the RV, left ventricle (LV) or in the liver. Hence, hypoxia-induced ER-β up-regulation appears to be lung-specific. Ex vivo, hypoxia exposure time-dependently up-regulated ER-β but not ER-α in cultured primary rat pulmonary artery endothelial cells (RPAECs) exposed to hypoxia (1% O2) for 4, 24 or 72h. Furthermore, the hypoxia induced ER-β protein abundance, while not accompanied by increases in its own transcript, was associated with ER-β nuclear translocation, suggesting increase in activity as well as post-transcriptional up-regulation of ER-β. Indeed, the requirement for ER-β activation was indicated in hypoxic ER-βKO mice where administration of E2 failed to inhibit hypoxia-induced pro-proliferative ERK1/2 signaling. Interestingly, HIF-1α accumulation was noted in lung tissue of hypoxic ER-βKO mice; consistent with previously reported negative feedback of ER-β on HIF-1α protein and transcriptional activation. In RAPECs, HIF-1 stabilization and overexpression did not replicate the effects of ER- β up-regulation seen in gas hypoxia; suggestive that HIF-1α is not sufficient for ER-β up- regulation. Similarly, HIF-1 inhibition with chetomin did not result in ER-β down-regulation. HIF-1α knockdown in RPAECs in hypoxic conditions is currently being investigated. Hypoxia increases ER- β, but not ER-α in the lung and lung vascular cells. Interpreted in context of beneficial effects of E2 on hypoxic PA and RV remodeling, our data suggest a protective role for ER-β in HPH. The mechanisms by which hypoxia increases ER-β appears to be post-transcriptional and HIF-1α independent. Elucidating hypoxia-related ER-β signaling pathways in PAECs may reveal novel therapeutic targets in HPH.
Eosinophils Are Recruited in Response to Chitin Exposure and Enhance Th2-Mediated Immune Pathology in Aspergillus fumigatus Infection
(American Society for Microbiology (ASM), 2014-08) O'Dea, Evan M.; Amarsaikhan, Nansalmaa; Li, Hongtao; Downey, Joshua; Steele, Emery; Van Dyken, Steven J.; Locksley, Richard M.; Templeton, Steven P.; Department of Microbiology & Immunology, IU School of Medicine
In patients infected with the fungus Aspergillus fumigatus, Th1 responses are considered protective, while Th2 responses are associated with increased morbidity and mortality. How host-pathogen interactions influence the development of these protective or detrimental immune responses is not clear. We compared lung immune responses to conidia from two fungal isolates that expressed different levels of the fungal cell wall component chitin. We observed that repeated aspirations of the high-chitin-expressing isolate Af5517 induced increased airway eosinophilia in the lungs of recipient mice compared to the level of eosinophilia induced by isolate Af293. CD4+ T cells in the bronchoalveolar lavage fluid (BALF) of Af5517-aspirated mice displayed decreased gamma interferon secretion and increased interleukin-4 transcription. In addition, repeated aspirations of Af5517 induced lung transcription of the Th2-associated chemokines CCL11 (eotaxin-1) and CCL22 (macrophage-derived chemokine). Eosinophil recruitment in response to conidial aspiration was correlated with the level of chitin exposure during germination and was decreased by constitutive lung chitinase expression. Moreover, eosinophil-deficient mice subjected to multiple aspirations of Af5517 prior to neutrophil depletion and infection exhibited decreased morbidity and fungal burden compared to the levels of morbidity and fungal burden found in wild-type mice. These results suggest that exposure of chitin in germinating conidia promotes eosinophil recruitment and ultimately induces Th2-skewed immune responses after repeated aspiration. Furthermore, our results suggest that eosinophils should be examined as a potential therapeutic target in patients that mount poorly protective Th2 responses to A. fumigatus infection.
FIBCD1 Binds Aspergillus fumigatus and Regulates Lung Epithelial Response to Cell Wall Components
(Frontiers, 2018-09-18) Jepsen, Christine Schoeler; Dubey, Lalit Kumar; Colmorten, Kimmie B.; Moeller, Jesper B.; Hammond, Mark A.; Nielsen, Ole; Schlosser, Anders; Templeton, Steven P.; Sorensen, Grith L.; Holmskov, Uffe; Microbiology and Immunology, School of Medicine
Aspergillus fumigatus (A. fumigatus) is a ubiquitous fungus of clinical importance associated with development of various pulmonary diseases and allergic hypersensitivity reactions. It is protected against environmental stress by a cell wall that contains polysaccharides such as chitin. We previously demonstrated that fibrinogen C domain-containing protein 1 (FIBCD1) is a membrane-bound protein that binds chitin through a conserved S1 binding site and is expressed in intestinal epithelium and salivary glands. Here, we further localized FIBCD1 protein expression at the surface of bronchial and alveolar human lung epithelium, observed recognition of A. fumigatus cell wall with S1 site-independent recognition. We observed FIBCD1-mediated suppression of IL-8 secretion, mucin production, and transcription of genes associated with airway inflammation and homeostasis in FIBCD1-transfected lung epithelial cells. These modulations were generally enforced by stimulation with A. fumigatus cell wall polysaccharides. In parallel, we demonstrated a FIBCD1-mediated modulation of IL-8 secretion induced by TLR2,-4, and -5. Collectively, our findings support FIBCD1 as a human lung epithelial pattern recognition receptor that recognizes the complex A. fumigatus cell wall polysaccharides and modulates the lung epithelial inflammatory response by suppressing inflammatory mediators and mucins.
Generation of mice carrying a knockout-first and conditional-ready allele of transforming growth factor beta2 gene
(Wiley, 2014-09) Ahmed, A. S. Ishtiaq; Bose, Gracelyn C.; Huang, Li; Azhar, Mohamad; Department of Pediatrics, Indiana University School of Medicine
Transforming growth factor beta2 (TGFβ2) is a multifunctional protein which is expressed in several embryonic and adult organs. TGFB2 mutations can cause Loeys Dietz syndrome, and its dysregulation is involved in cardiovascular, skeletal, ocular, and neuromuscular diseases, osteoarthritis, tissue fibrosis, and various forms of cancer. TGFβ2 is involved in cell growth, apoptosis, cell migration, cell differentiation, cell-matrix remodeling, epithelial-mesenchymal transition, and wound healing in a highly context-dependent and tissue-specific manner. Tgfb2(-/-) mice die perinatally from congenital heart disease, precluding functional studies in adults. Here, we have generated mice harboring Tgfb2(βgeo) (knockout-first lacZ-tagged insertion) gene-trap allele and Tgfb2(flox) conditional allele. Tgfb2(βgeo/βgeo) or Tgfb2(βgeo/-) mice died at perinatal stage from the same congenital heart defects as Tgfb2(-/-) mice. β-galactosidase staining successfully detected Tgfb2 expression in the heterozygous Tgfb2(βgeo) fetal tissue sections. Tgfb2(flox) mice were produced by crossing the Tgfb2(+/βgeo) mice with the FLPeR mice. Tgfb2(flox/-) mice were viable. Tgfb2 conditional knockout (Tgfb2(cko/-) ) fetuses were generated by crossing of Tgfb2(flox/-) mice with Tgfb2(+/-) ; EIIaCre mice. Systemic Tgfb2(cko/-) embryos developed cardiac defects which resembled the Tgfb2(βgeo/βgeo) , Tgfb2(βgeo/-) , and Tgfb2(-/-) fetuses. In conclusion, Tgfb2(βgeo) and Tgfb2(flox) mice are novel mouse strains which will be useful for investigating the tissue specific expression and function of TGFβ2 in embryonic development, adult organs, and disease pathogenesis and cancer. genesis
HIV envelope protein gp120-induced apoptosis in lung microvascular endothelial cells by concerted upregulation of EMAP II and its receptor, CXCR3
(American Physiological Society (APS), 2014-02-15) Green, Linden A.; Yi, Ru; Petrusca, Daniela; Wang, Ting; Elghouche, Alhasan; Gupta, Samir K.; Petrache, Irina; Clauss, Matthias; Department of Cellular & Integrative Physiology, IU School of Medicine
Chronic lung diseases, such as pulmonary emphysema, are increasingly recognized complications of infection with the human immunodeficiency virus (HIV). Emphysema in HIV may occur independent of cigarette smoking, via mechanisms that are poorly understood but may involve lung endothelial cell apoptosis induced by the HIV envelope protein gp120. Recently, we have demonstrated that lung endothelial apoptosis is an important contributor to the development of experimental emphysema, via upregulation of the proinflammatory cytokine endothelial monocyte-activating polypeptide II (EMAP II) in the lung. Here we investigated the role of EMAP II and its receptor, CXCR3, in gp120-induced lung endothelial cell apoptosis. We could demonstrate that gp120 induces a rapid and robust increase in cell surface expression of EMAP II and its receptor CXCR3. This surface expression occurred via a mechanism involving gp120 signaling through its CXCR4 receptor and p38 MAPK activation. Both EMAP II and CXCR3 were essentially required for gp120-induced apoptosis and exposures to low gp120 concentrations enhanced the susceptibility of endothelial cells to undergo apoptosis when exposed to soluble cigarette smoke extract. These data indicate a novel mechanism by which HIV infection causes endothelial cell loss involved in lung emphysema formation, independent but potentially synergistic with smoking, and suggest therapeutic targets for emphysema prevention and/or treatment.
The HMGB1-RAGE axis mediates traumatic brain injury-induced pulmonary dysfunction in lung transplantation
(American Association for the Advancement of Science, 2014-09-03) Weber, Daniel J.; Gracon, Adam S.A.; Ripsch, Matthew S.; Fisher, Amanda J.; Cheon, Bo M.; Pandya, Pankita H.; Vittal, Ragini; Capitano, Maegan L.; Kim, Youngsong; Allete, Yohance M.; Riley, Amanda A.; McCarthy, Brian P.; Territo, Paul R.; Hutchins, Gary D.; Broxmeyer, Hal E.; Sandusky, George E.; White, Fletcher A.; Wilkes, David S.; Medicine, School of Medicine
Traumatic brain injury (TBI) results in systemic inflammatory responses that affect the lung. This is especially critical in the setting of lung transplantation, where more than half of donor allografts are obtained postmortem from individuals with TBI. The mechanism by which TBI causes pulmonary dysfunction remains unclear but may involve the interaction of high-mobility group box-1 (HMGB1) protein with the receptor for advanced glycation end products (RAGE). To investigate the role of HMGB1 and RAGE in TBI-induced lung dysfunction, RAGE-sufficient (wild-type) or RAGE-deficient (RAGE(-/-)) C57BL/6 mice were subjected to TBI through controlled cortical impact and studied for cardiopulmonary injury. Compared to control animals, TBI induced systemic hypoxia, acute lung injury, pulmonary neutrophilia, and decreased compliance (a measure of the lungs' ability to expand), all of which were attenuated in RAGE(-/-) mice. Neutralizing systemic HMGB1 induced by TBI reversed hypoxia and improved lung compliance. Compared to wild-type donors, lungs from RAGE(-/-) TBI donors did not develop acute lung injury after transplantation. In a study of clinical transplantation, elevated systemic HMGB1 in donors correlated with impaired systemic oxygenation of the donor lung before transplantation and predicted impaired oxygenation after transplantation. These data suggest that the HMGB1-RAGE axis plays a role in the mechanism by which TBI induces lung dysfunction and that targeting this pathway before transplant may improve recipient outcomes after lung transplantation.
Impairment of exercise hyperaemia in familial hypercholesterolaemia: complex interplay of vasodilators vs. vasoconstrictors
(Wiley, 2014-04-14) Tune, Johnathan D.; Department of Cellular & Integrative Physiology, IU School of Medicine

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