research

Gustavo Matute-Bello

Associate Professor of Medicine

MD

Faculty Web Page

Last updated: August 31, 2010

Research Focus

Our laboratory is interested in investigating the mechanisms of lung injury and repair; specifically, we seek to answer the question–what are the very first events that differentiate a normal injury response from the pathologic response of acute lung injury? Within this broad question, we have focused on a specific ligand/receptor system, the Fas/FasL system, which is composed of the membrane surface receptor Fas (CD 95) and its natural ligand, FasL. Previous work has shown that the Fas/FasL system plays an important role in the development of lung injury. Activation of Fas in the lungs results in a form of lung injury characterized by early neutrophilic alveolitis, permeability changes, and alveolar epithelial apoptosis, followed by a late phase characterized by collagen deposition. Mice lacking Fas have attenuation of the lung response to a number of challenges such as LPS, bacteria, and mechanical ventilation. Interestingly, bacterial clearance is also faster in Fas-deficient mice, and this is particularly true For gram-positive bacteria. Thus, the Fas/FasL system appears to be involved in the pathogenesis of lung injury and repair.

The mechanism behind these responses appear to involve not just apoptosis, but also modulation of inflammation. The production of inflammatory cytokines by the lung is markedly attenuated in Fas-deficient mice, and studies using mouse chimeras and also macrophage depletion have demonstrated that the cytokine response to Fas is not localized to macrophages but instead to a non-macrophage cell. A series of in vitro studies is suggesting that the inflammatory response to Fas activation occurs at the level of alveolar epithelial cells by a mechanism that is independent of FADD and that involves the adapter protein MyD88 with subsequent activation of the MAP kinase pathway. In turn, the fibrotic response to Fas requires expression of the metalloproteinase MMP 12 and matricellular protein cyr 61. Finally, the modulation of bacterial clearance by the Fas/FasL system is associated with impairment of pathogen phagocytosis by mechanisms still unclear.

A new line of research for laboratory involves the role of adult resident mesenchymal stem cells in the modulation of lung injury. We have currently isolated several lines of stem cells from a number of different murine strains and we are defining their responses to standardized challenges.

Finally, I also have a strong interest in training of international physicians in the area of pulmonary and critical care medicine. Despite the increasing interest in Global Health, very little effort is being dedicated to the training of physician scientists in low-income countries, in particular individuals with the ability to identify health problems, develop strategies to solve his problems, and evaluate the success of these strategies. We are working with colleagues at some international settings to try to develop training programs that will help satisfy this need.

Relevant Publications

Bem RA, van Woensel JB, Bos AP, Koski A, Farnand AW, Domachowske JB, Rosenberg HF, Martin TR, Matute-Bello G. Mechanical ventilation enhances lung inflammation and caspase activity in a model of mouse pneumovirus infection. Am. J. Physiol Lung Cell Mol Physiol 2009; 296:L46-56 PMID 18996903.

Lipke AB, Matute-Bello G, Herrero R, Kurahashi K, Wong VA, Mongovin SM, Martin TR. Febrile-range hyperthermia augments lipopolysacharide-induced lung injury by a mechanism of enhanced alveolar epithelial cell apoptosis. J Immunol 184:7, 3801-13 (2010).

Bem RA, Farnand A, Wong V, Koski A, van Rooijen N, Frevert CW, Martin TR, Matute-Bello G. Depletion of resident alveolar macrophages does not prevent Fas-mediated lung injury in mice. Am J Physiol:Lung Cell Mol Physiol. 2008; 295:L314-25 PMID:18556802.

Matute-Bello G, Frevert CW, Martin TR. Animal Models of Acute Lung Injury. Am J Physiol Lung Cell Mol Physiol 2008, 295:L379-99. PMID 18621912

Chang DW, Hayashi S, Gharib S, Vaisar T, King ST, Tsuchiya M, Ruzinski JT, Park DR, Matute-Bello G, Wurfel MM, Bumgarner R, Heinecke JW, Martin TR. Proteomic and Computational Analysis of Bronchoalveolar Proteins During the Course of the Acute Respiratory Distress Syndrome, Am J Respir Crit Care Med, 2008; 178:701-9 PMID 18658106.

Chang DW, Colucci G, Vaisar T, King T, Hayashi S, Matute-Bello G, Bumgarner R, Heinecke J, Martin TR, Domenighetti GM. Proteomic analysis of two non-bronchoscopic methods of sampling the lungs of patients with the Acute Respiratory Distress Syndrome (ARDS). Clinical Proteomics 2007; DOI 10.1007/s12014-007-9002-8.

Matute-Bello G, Wurfel MM, Lee JS, Park DR, Frevert CW, Madtes DK, Shapiro SD, Martin TR. Essential role of MMP-12 in Fas-induced fibrosis. Am J Respir Cell Mol Biol 2007;37:210-221

Matute-Bello G, Lee JS, Liles WC, Frevert CW, Mongovin S, Wong V, Ballman K, Sutlief S, Martin TR. Fas-mediated acute lung injury requires Fas expression on non-myeloid cells of the lung. J Immunol 2005;175:4069-4075.

Matute-Bello G, Liles WC,, Frevert CW, Dhanireddy S, Ballman K, Wong V, Green RR, Song HY, Witcher DR, Jakubowski JA, Martin TR. Blockade of the Fas/FasL system improves pneumococcal clearance fron the lung without preventing bacteremic dissemination to the spleen. J Infect Dis. 2005 Feb 15;191(4):596-606.

Altemeier WA, Matute-Bello G, Gharib SA, Glenny RW, Martin TR, Liles WC. Modulation of LPS-induced gene transcription and promotion of lung injury by mechanical ventilation. J Immunol 2005;175:3369-3376.

 

 


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