National Heart, Lung, and Blood Institute program in
Acute Lung Injury
Specialized Centers of Clinically Oriented Research (ALI SCCOR)

Acute lung injury (ALI) and the Acute Respiratory Distress Syndrome (ARDS) are a common response to many lung specific and systemic insults. The incidence of ALI/ARDS may be as high as 75 per 100,000 population annually in the USA, and mortality in this disorder remains high. During ALI and ARDS, an overlapping continuum of injury, fibroproliferation and repair exists. The lung defends itself against microbes and other injurious substances by the generation of protective innate immune responses. The lung also has a substantial capacity to repair itself and restore normal architecture following an acute injury. However, the factors which determine the severity of injury, and whether injury culminates in death, fibrosis, or repair remain unclear. Studies using animal models and in patients with ALI/ARDS have shown that a complex regulatory network of inflammatory and regulatory molecules are produced within the lung and systemically by myeloid cells, lung epithelial cells, endothelial cells, and fibroblasts. Studies performed at the University of Michigan under funding from our previous SCOR in Acute Lung Injury identified functional abnormalities that alter autocrine and paracrine regulatory loops that control inflammatory cell and fibroblast accumulation, activation, and survival, as well as host defenses against microbes. The current University of Michigan SCCOR application capitalizes on animal and clinical studies performed over the last several years of SCOR funding and have been designed studies to test the following Central Hypothesis:

Concurrent induction of inflammatory and regulatory factors occurs in the lungs of patients with ALI/ARDS. A cytokine imbalance in these factors triggers the acute exudative phase of ALI/ARDS and creates an alveolar milieu which favors impaired pulmonary innate immune responses and fibroproliferative repair responses.

The Program Director of the University of Michigan SCCOR is Theodore J. Standiford, M.D. The Michigan SCCOR is composed of four hypothesis-driven projects, an Administrative Core, and two distinct but integrated Clinical Cores based at both the University of Michigan and Emory University Hospitals. A brief synopsis of each project is as follows:

Project I: Dynamic Effects of Chemokines on Systemic Inflammation; Steven L. Kunkel, PI.

Systemic inflammatory response syndrome (SIRS) is a critical condition developing in patients with severe injury resulting from major surgical insult, trauma, extensive burns, and sepsis. The local and systemic exuberant production of cytokines, at multiple levels, appears to be critical in the progression of this syndrome. Recent evidence suggests that cytokines and chemokines and their receptors participate in the initiation, maintenance, and resolution of this systemic insult. This project focuses on the role of the chemokine receptor CCR4 and its ligand CCL17 (TARC), an interaction that may result in immunoregulation of the host's response and could participate in various aspects of SIRS induced pathology. Preliminary studies suggest that TARC may play an important role in dampening the magnitude of local and systemic inflammation during innate immune responses to microbial challenge. The aims in this project will test the hypothesis that the expression of the chemokine TARC and its receptor CCR4 by structural cells and leukocytes represent key regulatory components of the septic response by modulating early cytokine production, toll-like receptor expression, and leukocyte activation/recruitment. Animal models of abdominal sepsis will be utilized to determine the cellular sources and contributions of CCR4 and it’s ligands to sepsis-induced leukocyte activation and tissue injury. These studies will be extended to human disease using BAL fluid and cells obtained from patients with ALI/ARDS. The experimental model systems coupled with an assessment of patient samples will provide a two pronged strategy to determine the balance of specific chemokines and their receptors during the evolution of systemic inflammation, and by doing so may identify novel targets for immune intervention in the treatment of this disease (for more information see project abstract).

Project 2: Macrophage Activation/Deactivation in ALI; Theodore J. Standiford, PI.

A hallmark of ALI/ARDS is exuberant pulmonary inflammation and injury to the alveolar-capillary membrane, which can result in dysregulated lung repair (fibroproliferation) and the development of nosocomial infection, particularly pneumonia. While the exact mechanism(s) that control intraalveolar inflammation in acute lung injury (ALI) remains unclear, dysregulation of alveolar macrophage function is believed to play a central role in disease pathogenesis. Recently, peroxisome proliferator-activated receptor-gamma (PPAR-g ), a member of the nuclear receptor superfamily of ligand-dependent transcription factors, has been shown to down-regulate the expression of inflammatory mediators from monocytes/macrophages. The studies in Project 2 have focused on PPAR-g because preliminary data have identified this transcription factor as a critical regulator of alveolar macrophage effector cell function and alveolar macrophage-mediated inflammation in ALI. The hypothesis of Project 2 is that the activation state of alveolar macrophages in ALI is regulated by PPAR-g , which functions to dampen the magnitude of alveolar macrophage inflammatory responses in ALI. Furthermore, it is postulated that determining the activation state of alveolar macrophages during the course of ALI may serve as an independent predictor of subsequent clinical outcomes in this disease. In Aims 1 and 2 of this project, an animal model of FITC-induced lung injury will be utilized to assess the expression, regulation, and function of PPAR-g in experimental lung injury. In studies using samples collected from patients with ALI/ARDS, PPAR-g expression/activity in alveolar macrophages will be correlated with the magnitude of pulmonary inflammation, the expression of endogenous ligands, and clinical outcomes in these patients. Additionally, the contribution of PPAR-g to functional alveolar macrophage phenotypic changes will be determined using inhibitor experiments. In final studies, we will determine if specific loss of function polymorphisms in PPAR-g alter disease susceptibility and/or clinical course of disease in patients with ALI/ARDS. Collectively, the studies proposed in Project 2 will provide novel insights into the role of PPAR-g in regulating alveolar macrophage inflammatory responses that are critical to the pathogenesis of ALI (for more information see project abstract).

Project 3: Alveolar Mesenchymal Cells in Acute Lung Injury; Victor J. Thannickal, PI.

Fibroproliferation is a common response to lung injury. While a fibroproliferative response is required for adequate repair of the injured alveolar-capillary membrane, this response must be appropriately controlled and is often dysregulated in the setting of ALI/ARDS. Events that promote exuberant fibroproliferation in ALI/ARDS have been incompletely defined, but are almost certainly linked to alterations in the phenotype of fibroblasts and other structural cells of the lung. Preliminary studies have identified cells in the alveolus of ALI/ARDS patients that express fibroblast differentiation markers. Furthermore, the phenotype of these cells is altered in patients with fibroproliferative ARDS, and the presence and/or phenotype of these alveolar mesenchymal cells may be predictive of dysregulated lung repair. These observations served to formulate the hypothesis that fibroblast progenitor cells are present in the alveolus of patients with ALI, and the phenotype of these cells is controlled by both genetic and microenvironmental factors. Furthermore, the presence and/or phenotype of alveolar mesenchymal cells are predictive of acute and long-term outcomes in patients with ALI/ARDS. Initial studies will be performed to determine the contribution of TGF-b to mesenchymal cell activation, differentiation, and apoptotic responses. Additional studies will be performed to determine the influence of environmental factors (oxidant stress) and genetic factors (gain in function TGF-b polymorphisms) on these responses. Finally, studies are ongoing to determine if the number and/or phenotype of alveolar mesenchymal cells present within the airspace of ALI/ARDS patients is predictive of persistent ARDS and other adverse clinical outcomes. Collectively, these studies are especially exciting because it is the first time that the biology and clinical implications of fibroblasts isolated from the airspace of patients with ARDS can be addressed (for more information see project abstract).

Project 4: A Randomized Trial of GM-CSF in Patients with ALI; Robert Paine, III, PI.

Despite significant progress in intensive care unit care and ventilator management, respiratory failure due to ALI and ARDS remains a major health problem, with unacceptably high mortality despite enormous expenditure of health care resources. Survivors face long term consequences for quality of life. New therapies are needed both to improve early survival and to decrease long term sequelae of this syndrome. Granulocyte-macrophage colony stimulating factor (GM-CSF) is a naturally occurring cytokine that is present in the normal lung, with important roles in pulmonary homeostasis. GM-CSF is essential for normal maturation and function of alveolar macrophages, resident inflammatory cells that are responsible for initial defense against pneumonia. Alveolar epithelial cells line the gas exchange surface of the lung. Injury and delayed repair of damage to this epithelium is an important mechanism of acute lung injury and subsequent abnormal healing, leading to pulmonary fibrosis. GM-CSF has potent effects on alveolar epithelial cells, promoting proliferation and limiting epithelial cell death. Thus, GM-CSF has a distinctive combination of activities making it an excellent candidate for a therapeutic intervention in ALI/ARDS. Preliminary studies for this project demonstrate that GM-CSF can protect experimental animals against acute lung injury, can decrease susceptibility to pneumonia, and is protective against pulmonary fibrosis following acute lung injury. There is extensive experience with the administration of recombinant human GM-CSF to human patients; this biological is approved by the FDA has been well-tolerated in trials involving critically ill patients. This project is based on the hypothesis that administration of GM-CSF will improve clinical outcomes for patients with ALI/ARDS. A randomized, placebo-controlled trial of GM-CSF is being performed to determine whether treatment with GM-CSF for 14 days will shorten the duration of mechanical ventilation for patients with ALI/ARDS, allowing patients to breath without ventilator support earlier in their course. Additional endpoints to be evaluated include effects on the incidence of newly acquired pneumonia in the ICU, mortality, and parameters of alveolar macrophage and alveolar epithelial cell function. Finally, quality of life and incidence of pulmonary fibrosis after 6 months will be assessed in survivors. Patients enrolled in this study will receive mechanical ventilation according to a standardized protocol. Periodically, they will have blood drawn and undergo bronchoscopy for studies to evaluate in more detail the mechanisms of GM-CSF effects. When completed, these Specific Aims will determine whether treatment with recombinant GM-CSF will improve outcome in these critically ill patients, and will determine through which of several potential mechanisms GM-CSF is acting (for more information see project abstract).

Core A: Clinical Core; Robert C. Hyzy, PI; Ronald E. Dechert, Project Manager; Marc Moss and Gregory S. Martin, PI and Co-PI at the Emory University Site, respectively).

Core A represents a unique and exciting consortium between the University of Michigan  and Emory University,  a union that brings together a wealth of knowledge, experience, resources, and an impressive patient base with complementary population demographics. The University of Michigan Medical Center is an 886-bed tertiary care facility with 80 ICU beds. The Emory Lung Research Network at Emory consists of three hospitals in the Atlanta area, with a total of over 170 ICU beds. Collectively, the Core has been constructed to accomplish the multiple missions of the SCCOR. The Clinical Core will provide each project with human samples and the clinical database to correlate their findings with specific clinical outcomes in ALI/ARDS patients. These samples are provided to the investigative projects only in a fashion that will not unblind the randomized therapeutic trial. In addition, biological samples and clinical data collected will be made available to other ALI SCCOR Centers as needed (for more information see project abstract).

Administrative Core: Theodore Standiford, PI; Mary Malec, Program Coordinator

Theodore J. Standiford, M.D. serves as the Program Director and the PI of the Administrative Core. This Core oversees all administrative aspects of the University of Michigan ALI SCCOR. Functions of the Core include coordinating meetings and communication between all of the projects and the Clinical Cores at the University of Michigan and our consortium site at Emory University. In addition, the Administrative Core handles all financial aspects of the program and interacts with both internal and external regulatory agencies to ensure adequate communication, documentation and compliance. Finally, the Core is instrumental in arranging SCCOR investigator travel, visiting lectureships, and semi-annual SCCOR meetings in conjunction with other ALI SCCOR programs (for more information see project abstract).

In sum, our SCCOR represents a unique multidisciplinary and multicenter collaboration that unites a diverse group of investigators with expertise in the clinical and basic investigation of ALI, as well as provides access to a large population of ALI/ARDS patients to ensure successful completion of the proposed studies. The performance of studies proposed in this application will provide important insights into the regulation of pulmonary inflammation and repair in ALI, which may lead to novel approaches in both the assessment and treatment of this devastating disease. This bench to bedside approach has already culminated in a therapeutic trial assessing the effect of one such factor (GM-CSF) in the treatment of patients with ALI/ARDS.

Theodore J. Standiford, M.D.

Steven L. Kunkel, Ph.D.

Victor J. Thannickal, M.D.

Robert Paine III, M.D.

Robert C. Hyzy, M.D.

Marc Moss, M.D.

Gregory S. Martin, M.D., M.Sc.

Ronald E. Dechert, R.R.T., Ph.D.

Mary A. Malec