Lung Biology Laboratory
We study the cell and molecualr biology of lung inflammation by real-time fluorescence imaging. Severe, rapidly progressing lung inflammation causes acute lung injury, a debilitating condition that usually requires intensive care therapy under mechanical ventilation. It is estimated that about 250,000 people suffer from acute lung injury in the US alone, with a mortality rate of 20-25%. Patients who survive the disease continue to have a high rate of morbidity for many years. Despite these statistics, there is really no "cure" for acute lung injury in the sense that one cannot administer an agent that reverses the illness or blocks its progress. The available therapy continues to be of the supportive kind in which the patient's physiological deterioration is kept in check.
Prime causes of acute lung injury are infection and sepsis. According to the WHO, lower respiratory tract infections are the fifth largest cause of death in high-income countries and the third largest cause worlwide. Other causes inlcude gastric acid aspiration, lung barotrauma, pulmonary embolism and smoke inhalation. These conditions can be replicated in animal models, providing a means to understand basic disease mechanisms and to develop products that might be therapeutically effective in the clinical setting.
Jahar Bhattacharya, M.D., D.Phil.
Professor of Medicine
Professor of Physiology and Biophysics
Real-time fluorescence imaging of the lung
We specialize in single and two-photon laser scanning microscopy of the intact lung. Many of these methods were originally developed by our group. In situ optical methods provide direct access to the alveolo-capillary region, the site of the inflammation in acute lung injury. This access has enabled us to address several alveolo-capillary issues that relate to the pathology of acute lung injury, inlcuding calcium regulation, alveolar micromechanics, mitochondrial biology, cell-cell communication, and alveolar secretory function.
Freshly isolated lung endothelial cells (FLEC)
To study interactions of platelets and leukocytes with the lung endothelium in disease models, we developed the FLEC approach. Lung endothelial cells are freshly isolated under chilled conditions to preserve their in situ responses that are studies by confocal microscopy, immunoblotting and PCR.
Cultured endothelial cells
Endothelial cells are cultured as monolayers or in 3D collagen gels for studies of focal adhesions, cadherins and connexins.
We developed a method for chemically conjugating the TAT peptide with his-tagged proteins intended as cargo for intracellular delivery.
Some recent findings
- "Pacemaker" endothelial cells generate propagating calcium waves in the capillary wall .
- Ying X, Minamiya Y, Fu C, Bhattacharya J. Ca2+ waves in lung capillary endothelium. Circ Res. 1996 Oct;79(4):898-908. PMID: 8831516
- Kuebler WM, Ying X, Singh B, Issekutz AC, Bhattacharya J. Pressure is proinflammatory in lung venular capillaries. J Clin Invest. 1999 Aug;104(4):495-502. PMID: 10449441
- Alveoli regulate expression of leukocyte adhesion receptors (Kuebler WM et al., 2000) and nitric oxide production (Kiefmann R. et al., 2009) in capillaries.
- Kuebler WM, Parthasarathi K, Wang PM, Bhattacharya J. A novel signaling mechanism between gas and blood compartments of the lung. J Clin Invest. 2000 Apr;105(7):905-13. PMID: 10749570
- Kiefmann R, Islam MN, Lindert J, Parthasarathi K, Bhattacharya J. Paracrine purinergic signaling determines lung endothelial nitric oxide production. Am J Physiol Lung Cell Mol Physiol. 2009 Jun;296(6):L901-10. PMID: 19304909
- Mechanosensing cells intercommunicate with secretory epithelial cells to regulate alveolar surfactant release.
- Hyperosmolar sucrose increases the endothelial barrier (Safdar Z. et al., 2003) and blocks lung capillary inflammation (Safdar Z. et al., 2005) .
- Safdar Z, Wang P, Ichimura H, Issekutz AC, Quadri S, Bhattacharya J. Hyperosmolarity enhances the lung capillary barrier. J Clin Invest. 2003 Nov;112(10):1541-9. PMID: 14617755
- Safdar Z, Yiming M, Grunig G, Bhattacharya J. Inhibition of acid-induced lung injury by hyperosmolar sucrose in rats. Am J Respir Crit Care Med. 2005 Oct 15;172(8):1002-7. PMID: 16109982
- Intercellular communication through endothelial connexin 43 regulates vascular permeability.
- Lung barotrauma due to high volume mechanical ventilation causes endothelial focal adhesion formation and deposition of platelet proteins on the endothelium, rendering a pro-coagulant phenotype to the vasculature.
- Bhattacharya S, Sen N, Yiming MT, Patel R, Parthasarathi K, Quadri S, Issekutz AC, Bhattacharya J. High tidal volume ventilation induces proinflammatory signaling in rat lung endothelium. Am J Respir Cell Mol Biol. 2003 Feb;28(2):218-24. PMID: 12540489
- High doses of bone marrow-derived mesenchymal cells shrinks
- Red cells release peroxide in lung hypoxia.
- Edema contracts alveoli.
- Endothelial mitochondria determine inflammation severity.
The high mortality associated with acute lung injury is attributed to the injurious effects of mechanical ventilation on alveoli. However, the micromechanical basis of these injuries is unknown. In a single-alveolus model of pulmonary edema, unexpected micromechanical effects ensue when air-filled and liquid-filled alveoli are juxtaposed. The liquid-filled alveolus shrinks, imposing mechanical stress on its air-filled neighbor. The mechanical stress reduces compliance of the air-filled alveolus, making it a target for overexpansion injury.
Text about calcium regulation in the lung.
Endothelial cell junctions determine vascular barrier properties and are subject to transient opening to allow liquid flux from blood to tissue. Although endothelial cell junctions open in the presence of permeability-enhancing factors, including oxidants, the mechanisms by which they reseal remain inadequately understood. Our studies address the unanswered question of how open endothelial cell junctions reseal.
Alveolar Secretory Function
The liquid layer lining the pulmonary alveolar wall critically determines the lung's immune defense against inhaled pathogens, because it provides a liquid milieu in the air-filled alveolus for dispersal of immune cells and defensive surfactant proteins. However, mechanisms underlying formation of the liquid are unknown. We achieve visualization of the alveolar wall liquid (AWL) in situ in mouse lungs by means of optical-sectioning microscopy.
Text about mitochondria studies here.
Our goal is to develop a protein-based therapy for endothelial cell barrier enhancement to prevent pulmonary edema in the context of acute lung injury. We introduce barrier-enhancing proteins using cell-permeable peptides in endothelial cells of lung microvessels.
- Rowlands, D.J., Das S., Huertas A., Islam M.N., Quadri S.K., Horiuchi K., Inamdar N., Emin M., Lindert J., Bhattacharya S. and Bhattacharya J. Mitochondrial Ca2+ oscillations determine severity of inflammation by activating TNFR1 ectodomain shedding in mouse lung microvessels. J Clin Invest. 2011 May 2;121(5):1986-99. PMID: 21519143.
- Bhattacharya J. Seeing is believing. Nat Methods. 2011 Jan;8(1):57-8. PMID: 21191375.
- Perlman C.E., Lederer D.J., Bhattacharya J. The micromechanics of alveolar edema. Am J Resp Cell Mol Biol.2011. 44:34-9. PMID: 20118224.
- Otsu K., S. Das, Houser S.D., Quadri S.K., Bhattacharya S., Bhattacharya J. Concentration-dependent inhibition of angiogenesis by mesenchymal stem cells. Blood. Apr 30 2009;113(18):4197-4205. PMID: 19036701. Editorial Comment: M. Matthay. “Mesenchymally stemming angiogenesis.”
- Kiefmann R., Islam M.N., Lindert J., Parthasarathi K., Bhattacharya J. Paracrine purinergic signaling determines lung endothelial nitric oxide production. Am J Physiol Lung Cell Mol Physiol. Jun 2009; 296(6):L901-910. PMID: 19304909.
- Quadri S.K. and Bhattacharya J. Resealing of endothelial junctions by focal adhesion kinase. Am J Physiol Lung Cell Mol Physiol. Jan 2007;292(1):L334-342. PMID: 17012369.
- Perlman C.E and Bhattacharya J. Alveolar expansion imaged by optical sectioning microscopy. J Appl Physiol. Sep 2007;103(3):1037-1044. PMID: 17585045.
- Lindert J., Perlman C.E., Parthasarathi K., Bhattacharya J. Chloride-dependent secretion of alveolar wall liquid determined by optical-sectioning microscopy. Am J Respir Cell Mol Biol. Jun 2007;36(6):688-696. PMID: 17290033.
- Kuebler W.M., Parthasarathi K., Lindert J., Bhattacharya J. Real-time lung microscopy. J Appl Physiol. Mar 2007;102(3):1255-1264. PMID: 17095639.
- Parthasarathi K., Ichimura H., Monma E., Lindert J., Quadri S.K. Issekutz A., Bhattacharya J. Connexin 43 mediates spread of Ca2+-dependent proinflammatory responses in lung capillaries. J Clin Invest. Aug 2006;116(8):2193-2200. PMID: 16878174.
- Ichimura H., Parthasarathi K., Lindert J., Bhattacharya J. Lung surfactant secretion by interalveolar Ca2+ signaling. Am J Physiol Lung Cell Mol Physiol. Oct 2006;291(4):L596-601. PMID: 16698857.
- 11. Islam MN, S Das, MT Emin, M Wei, L Sun, K Westphalen, D Rowlands, S Quadri, S Bhattacharya, J Bhattacharya. Mitochondrial transfer from bone marrow-derived mesenchymal stromal cells to pulmonary alveoli protects against acute lung injury. Nat Med. 2012. 18:759-765. PMID:22504485
- 12. Kristin Westphalen, Eiji Monma, Mohammad N. Islam & Jahar Bhattacharya. Acid contact in the rodent pulmonary alveolus causes proinflammatory signaling by membrane pore formation. Am. J. Physiol. Lung Cell Mol. Physiol. 2012. 303:L107-16. PMID:22561462
- 13. Emin, Memet T, Li Sun, A Huertas, S Das, J Bhattacharya, S Bhattacharya. Platelets induce endothelial tissue factor expression in a mouse model of acid-induced lung injury. Am. J. Physiol. Lung Cell Mol. Physiol. 2012 Jun 1;302(11):L1209-20. PMID:22505671
- 14. Quadri S, Sun L, Islam MN, Shapiro L, Bhattacharya J. Cadherin selectivity filter regulates endothelial sieving properties. Nat Commun. 2012;3:1099. PMID:23033075
- 15. Huertas, A., Das, S., Emin M., Rifkind JM, J. Bhattacharya and S. Bhattacharya. Erythrocytes induce proinflammatory endothelial activation in hypoxia. Am J Respir Cell Mol Biol. 2013 Jan;48(1):78-86. PMID:23043086.
Jahar Bhattacharya, MD, DPhil
Sadiqa K. Quadri, PhD
Shonit Ranjan Das, PhD
Sunita Bhattacharya, MD
M. Naeem Islam, PhD
Galina Gusarova, PhD
Kristin Westphalen, MD
Applications for postdoctoral positions in the laboratory are always welcome from outstanding candidates. Please email your CV, a brief description of your research interests as they relate to ongoing projects in the laboratory, and three letters of reference to email@example.com.
Postdoctoral training positions are also available yearly in the CU Training Program in Lung Science through the Division of Pulmonary, Allergy & Critical Care Medicine. This program is supported by an NIH Training Grant.
Graduate Student Positions:
Graduate students and MD/PhD students are welcome to rotate in the lab. Each student is assigned to a senior member of the lab and meets with the PI on a regular basis for mentoring. Interested students should email firstname.lastname@example.org.
Students interested in applying to the Department of Physiology and Cellular Biophysics should check out the graduate program web site. This program is supported by an NIH training grant.
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