The Problem


Inflammation is a complex biological process that occurs in response to harmful stimuli and whose function is to eliminate the cause of cell injury and initiate the repair process. Lung inflammation occurs in response to bacterial and viral pathogens and environmental pollutants. There exists a critical need to understand the mechanisms that lead to lung inflammation and develop novel strategies to treat unregulated lung inflammation. Several types of cells are involved in lung inflammation, including the epithelial cells that line the airways and alveoli and endothelial cells that line all the blood vessels on the lung. Airway epithelial cells and endothelial cells are important in the host defense system by acting as physical barriers as well as by secreting cytokines and chemokines that serve as inflammatory mediators, and growth factors that promote tissue repair and fibrosis. During the acute phase of inflammation, neutrophils rapidly migrate to the lung as first responders, producing reactive oxygen species and secreting serine proteases, matrix metalloproteinases, and other enzymes during degranulation. These products not only degrade invading dangers but also contribute to alveolar destruction. The number of T lymphocytes also increases and may contribute to the pathophysiology of lung inflammation.

          Produced by epithelial and inflammatory cells, cytokines and chemokines play a central role in the inflammatory process. In particular, tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) act as initiator cytokines by inducing the increased production of themselves and the synthesis of other cytokines, chemokines, and adhesion molecules, thereby attracting and activating immune cells at the site of inflammation. Soluble TNF-α then binds to the TNF receptor and activates the mitogen-activated protein kinase (MAPK) cascade and the nuclear factor-kappa B (NFkB) pathway after the ligand-bound receptor forms a protein complex with TNF receptor 1-associated death domain protein and TNF receptor-associated factor.  MAPKs are phosphorylated and activated by MAPK kinases, which in turn are activated by MAPK kinase kinases. MAPKs directly phosphorylate and activate transcription factors or they phosphorylate other kinases, which in turn activate transcription factors that lead to the expression of response genes; MAPKs also phosphorylate other substrates that are involved in many biological processes, including inflammation.

          Like TNF-α, IL-1β is initially synthesized as pro-IL-1β, an inactive precursor. Pro-IL-1β is then cleaved inside the cell by a protein complex called the inflammasome, which is composed of apoptosis-associated speck-like protein containing caspase recruitment domain, caspase-1, and a member of the nucleotide-binding oligomerization domain (NOD)-like receptor family.  Different NOD-like receptor members respond to different signals. One of these members, NOD-like receptor protein-3 (NLRP3), is recruited in response to tissue damage, metabolic stress, and infection.  Once pro-IL-1β is processed, the mature IL-1β product is secreted and binds to the IL-1 receptor. The ligand-bound receptor forms a complex with myeloid differentiation primary response 88, IL-1 receptor-associated kinase, and TNF receptor-associated factor-6, thereby activating the MAPK cascade and the NF-κB pathway.  Different mechanisms have been proposed for the activation of the inflammasome, including potassium efflux and the generation of reactive oxygen species, but both hypotheses have been challenged.  Other researchers have demonstrated the importance of autophagy and the P2X7 receptor in mediating the processing of IL-1β by the inflammasome.  Inflammation is usually resolved when the cause of the cell injury has been eliminated. Elucidating these pathways may serve to identify potential therapeutic targets susceptible to anti-inflammatory treatments.

          There is currently no cure for acute or chronic inflammatory lung disorders or effective treatment for severe lung inflammation observed ARDS, VILI, radiation pneumonitis as well as more mild but persistent lung inflammation seen in the dyregulated repair process seen in pulmonary fibrosis. The IL-1β pathway is increasingly recognized for its importance in lung inflammation. Elucidation of these mechanisms is facilitated by reviewing the research that has been performed on these different toxicants, and such understanding may facilitate the development of therapeutics that would be useful in treating acute and chronic lung inflammation such as ARDS, VILI, radiation pneumonitis as well as more mild but persistent lung inflammation seen in the dyregulated repair process seen in pulmonary fibrosis. Effective strategies that block inflammation may ultimately lead to successful treatment of ARDS, VILI, radiation pneumonitis as well as more mild but persistent lung inflammation seen in the dyregulated repair process seen in pulmonary fibrosis.

          Lung inflammation is a well-choreographed host defense mechanism to assure survival and is is essential to health. In the setting of bacterial, viral or fungal infection, invading microbes, noxious stimuli, or tissue injury, an acute inflammatory response is mounted to protect the host with these inflammatory pathways provide an exceedingly efficient mechanism to address the offending organism and to eliminate the threat while restoring lung balance. However, based upon a number of genetic, epigenetic and environmental factors, these pathways potentially become dysregulated leading to excessively intense and excessively prolonged and sustained lung inflammation, most often at a subtle level if a chronic condition, or exceptionally intense in the acute setting. The presence of both acute and chronic lung inflammation confers serious consequences for the individual including heightened of risk profound morbidities and death.

          In the acute setting, sepsis, trauma are major causes for development of respiratory failure and the ned for mechanical ventilation. Lung inflammation is a major driver of the for the need for mechanical ventilation and for the duration of support needed. Ventilator-induced lung injury is a serious contributor to the mortality of patients in the Intensive Care Units and to the 30-40% mortality of the acute respiratory distress syndrome or ARDS. There are no currently therapies for VILI and ARDS.

          To limit inflammation and prevent collateral injury of healthy, uninvolved tissue, the lung orchestrates the formation of specialized fibrosis-resolving molecules. Unfortunately, cessation of inflammatory processes often goes awry resulting in chronic lung inflammation and a stimulus for lung tissue remodeling of the lung tissue such as in a disease such as pulmonary fibrosis or a remodeling of the blood vessels in the lung as seen in pulmonary hypertension.

The Solution


Controlling lung inflammation is a vexing challenge in disorders with acute and chronic lung inflammation. lung inflammation a contributor to prognosis. In addition, the relationship between lung inflammation and cardiovascular disease is strong with chronic inflammation an under-recognized risk factor for cardiovascular disease. ALT scientists have long championed use of genomic–intensive approaches to identify novel genes as potential therapeutic targets in inflammatory lung disorders. These studies in preclinical models of acute and chronic inflammatory lung and disorders identified the gene encoding nicotinamide phosphoribosyltransferase (NAMPT) as a novel candidate gene and therapeutic target in ARDS, VILI, pulmonary hypertension and idiopathic pulmonary fibrosis.  As NAMPT is intimately involved in the development of acute and chronic lung inflammation to perpetuating the inflammatory response, targeting Nampt with a a highly-specific human monoclonal antibody, eNamptor™, that neutralizes NAMPT and reduces lung inflammation may influence acute and chronic lung disease outcomes lung tissue fibrotic pathways, vascular remodeling, severity and mortality.