Lung Biology Laboratory
Professor of Medicine, Physiology & Cellular Biophysics
Phone: 212-305-7310 (Office), 212-305-6724 (Lab)
Address: 630 W168th Street
Black Building 8-812
New York, NY10032
We study the cell and molecular biology of lung inflammation by real-time fluorescence imaging and multiple other approaches. Severe, rapidly progressing lung inflammation causes the disease called Acute Lung Injury (ALI), a debilitating condition in which there is breakdown of fluid barriers separating blood from the inhaled air, causing fluid accumulation in the lung’s airspaces. The resulting respiratory failure requires respiratory support by mechanical ventilators in critical care units. It is estimated that about 250,000 people suffer from ALI 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 ALI in the sense that one cannot administer an agent that reverses the illness or blocks its progress. The available therapy continues to be supportive in that the patient's physiological deterioration is kept in check.
Prime causes of ALI 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 worldwide. Other causes include 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.
Our ongoing projects include research in immunity, fluid barriers, barrier-enhancing biologics (we have patented one biologic), surfactant secretion, water secretion, micromechanics, stem cells and macrophages. In the last three years, our publications have appeared in high-impact journals, including the Journal of Clinical Investigation, Nature Communications, Nature Medicine and Nature. Despite the competitive times for federally supported research funding, we expect our research to grow considerably in the near future.
Jahar Bhattacharya, M.D., D.Phil.
Professor of Medicine
Professor of Physiology and Biophysics
Example images from real-time confocal fluorescence microscopy
Live views of alveoli and capillaries by confocal microscopy of a mouse lung. Images show the alveolar-capillary region of the lung. LEFT: Green dye shows vessels lying adjacent to an alveolus. RIGHT: High magnification shows epithelial cells (red) and an endothelial cell (green).
Live confocal image of mouse lung shows sessile alveolar macrophages (arrows) lying adjacent to alveolar septa (red). The macrophages communicate with alveolar epithelium through connexin-43 containing gap junctions. The junctions communicate counter-inflammatory calcium signals from macrophages to the epithelium (Westphalen, 2014)
Mitochondrial regulation of acute lung injury. One of our goals is to understand mitochondrial mechanisms underlying ALI. We reported that mitochondrial transfer from bone marrow-derived mesenchymal stem cells (BMSCs) to injured lung cells rescues ALI. Ongoing studies aim at molecular mechanisms underlying the mitochondrial protective effect.
Confocal image of alveoli in an endotoxin-treated lung shows alveoli containing airway-instilled bone marrow-derived stem cells (BMSCs). The colors depict alveolar septa (green), BMSC nuclei (blue) and BMSC mitochondria (red). The arrows point to regions at which BMSCs transferred mitochondria to epithelium (yellow). (Islam, 2012)
3-D alveolar geometry during lung inflation. The effect of lung volume on alveolar geometry impacts several aspects of lung function. Moreover, during lung expansion, the pattern of alveolar perimeter distension is an important determinant of lung functions as, for example, surfactant secretion. Using optical sectioning microscopy, this project aims to correlate inflation-induced changes in alveolar geometry with lung function.
Alveolar micromechanics. In a single-alveolus model of pulmonary edema, unexpected micromechanical effects ensue when air-filled and liquid-filled (green) 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 over-expansion injury. (Perlman, 2011).
Activated platelets deposit proteins on the endothelial surface. Confocal images show freshly isolated single endothelial cells from lungs exposed to low- (LV) or High- (HV) volume ventilation. P-selectin and vWf were deposited on the endothelial surface after HV, not LV. Platelet depletion (PDB) in blood (WB) blocked the effect. Deposition of these proteins provides a platform for coagulation and further injury (Yiming, 2008).
- Mechanism of surfactant secretion. Pulmonary surfactant maintains patency of alveoli, the sites of gas exchange in the lung. Vesiclescontaining surfactant in alveolar type 2 epithelial cells are held stationary by the actin cytoskeleton, while surfactant flows between the vesicles en route to the secretion locus in the plasma membrane (American Journal of Physiology: Lung, 2014).
- Differential cadherin mobility determines endothelial barrier properties. Real-time confocal imaging of endothelial junctions shows mobile cadherins that assemble at focal points in a F-actin dependent manner to establish the protein selectivity filter that determines endothelial sieving properties (Nature Communications, 2012).
- Red blood cells generate reactive species in lung hypoxia. Optically imaged lungs show that in hypoxia, erythrocytes flowing in lung microvessels generate peroxide that diffuses to the adjoining endothelium to induce proinflammatory activation (Blood, 2008; American Journal of Respiratory Cell & Molecular Biology, 2013)
- Acid injury. Acid aspiration, modeled in mouse lung by micropuncturing alveoli and delivering concentrated acid directly in the alveolar space, caused pore formation in the alveolar epithelium, leading to generation of reactive oxygen species and inflammatory outcomes (American Journal of Physiology: Lung, 2012).
- Lung endothelial mitochondrial calcium determines shedding of the luminal TNF-α receptor. Real-time confocal microscopy reveals that lung endothelial mitochondrial calcium increase induces TNF-α receptor shedding. The findings indicate that endothelial mitochondria determine the severity of soluble TNF-α-induced microvascular inflammation (J. Clin. Invest:2011).
- Mechano-induction of mitochondrial calcium. Vascular stretch induced by an increase in the vascular pressure causes calcium release from endosomal stores and increase of mitochondrial calcium. Mitochondrial peroxide diffuses to the cytosol to activate expression of proinflammatory receptors (J. Clin. Invest: 2003.)
- Protein therapy in ALI. We have developed a patented method for introducing purified, barrier-enhancing proteins in lung endothelium and alveolar epithelium. By this strategy, loading lung endothelium with focal adhesion kinase (FAK) protected against endotoxin-induced ALI.
- Real-time studies of alveolar actin. Sub-cortical actin can act as a fence to negatively regulate surface expression of pro-inflammatory receptors in alveoli. We developed methods for real-time actin determination in live alveoli. In this project, we aim to determine the physiological regulation of the alveolar F-actin fence and the extent to which enhancement of alveolar F-actin fence is protective in ALI.
- Liquid secretion in alveolar wall. Our goal in this project is to understand mechanisms underlying formation of the alveolar wall liquid (AWL), which constitutes the alveolar aqueous phase. The AWL enables surfactant phospholipids and proteins to distribute along the alveolar wall. As such it is critical for gas exchange and defense functions of the lung. However, factors underlying AWL formation are largely unknown.
- Westphalen K, Gusarova GA, Islam MN, Subramanian M, Cohen TS, Prince AS, Bhattacharya J. Sessile alveolar macrophages communicate with alveolar epithelium to modulate immunity. Nature. 2014:506 (7489):503-6. PMID:24463523
- Schumacker PT, Gillespie MN, Nakahira K, Choi AM, Crouser ED, Piantadosi CA, Bhattacharya J. Mitochondria in lung biology and pathology: more than just a powerhouse. Am J Physiol Lung Cell Mol Physiol. 2014. 306(11):L962-74. Review. PMID:24748601
- Huang SX, Islam MN, O'Neill J, Hu Z, Yang YG, Chen YW, Mumau M, Green MD, Vunjak-Novakovic G, Bhattacharya J, Snoeck HW. Efficient generation of lung and airway epithelial cells from human pluripotent stem cells. Nat Biotechnol. 2014. 32(1):84-91. PMID: 24291815.
- Islam MN, Gusarova, GA, Monma, E, Das SR, and Bhattacharya J. F-actin scaffold stabilizes lamellar bodies during surfactant secretion. Am J Physiol Lung Cell Mol Physiol 306: L50–L57, 2014. PMID:24213916
- Looney MR, Bhattacharya J. Live imaging of the lung. Annu Rev Physiol. 2014;76:431-45. 2013. Review. PMID: 24245941
- Matthay MA, Anversa P, Bhattacharya J, Burnett BK, Chapman HA, Hare JM, Hei DJ, Hoffman AM, Kourembanas S, McKenna DH, Ortiz LA, Ott HC, Tente W, Thébaud B, Trapnell BC, Weiss DJ, Yuan JX, Blaisdell CJ. Cell therapy for lung diseases. Report from an NIH-NHLBI workshop, Am J Respir Crit Care Med. 2013. 188(3)370-5. PMID: 23713908.
- Rogers RS, Bhattacharya J. When cells become organelle donors. Physiology (Bethesda). 2013 28(6):414-22. Review. PMID: 24186936.
- Islam MN, Das SR, Emin MT, Wei M, L Sun, Westphalen K, Rowlands D, Quadri S, Bhattacharya S, Bhattacharya J. 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
- Quadri S, Sun L, Islam MN, Shapiro L, Bhattacharya J. Cadherin selectivity filter regulates endothelial sieving properties. Nat Commun. 2012;3:1099. PMID:23033075
- 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
- 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
- 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
- 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.
Jahar Bhattacharya, MD, DPhil
Shonit Ranjan Das, PhD
Galina Gusarova, PhD
Rebecca Turcotte, MD, PhD
Kai Wu, MD
Sunita Bhattacharya, MD
Sadiqa K. Quadri, PhD
Naeem Islam, PhD
Jaime Hook, MD
John Odackal, MA
Benjamin Parker-Goos, BA
Dr. Bhattacharya is the director of an NIH-funded training program. The goal of this program is to train a new generation of postdoctoral MD and PhD scientists to become future leaders in the basic and translational investigation of major lung diseases. The emphasis is on lung biology with incorporation of molecular biology, genetics, epigenetics and molecular imaging. The spectrum of lung disease includes asthma, COPD, lung cancer, cystic fibrosis, sleep, acute lung injury, pediatric pulmonary disease, and immunologic pulmonary disease. The training program provides world-class mentorship in the sciences, training in competitive grant writing, and is committed to an educational environment designed to provide trainees with the necessary skills to become successful independent investigators.
The mentors are specialists in basic and translational lung research, as well as specialists from non-lung areas whose expertise bears on lung disease who have in total, trained 72 postdoctoral trainees in the last 10 years. Of these trainees, 39 hold advanced academic positions. For details of this training program, please contact Cicely Acosta (email@example.com).
630 W 168th St
New York, NY 10032
650 W 168th St
Black Building 8-812
Physicians & Surgeons 9-460
Physicians & Surgeons 8-425