In addition to the critical function of gas exchange, our lungs also serve as an important barrier between our bodies and the environment. The reviews in this series explore all aspects of the lung, from the developmental processes that generate the barrier, to the immune reactions that drive conditions like asthma, to the cell biology that underlies acute respiratory distress and pulmonary fibrosis. In a turn toward clinical medicine, this series also addresses how basic research has contributed to the development of new therapeutic strategies for pulmonary disease. Cover image credit: Shutterstock, Inc. Copyright: Sebastian Kaulitzki
The lung is a complex organ with multiple functions; in addition to facilitating gas exchange, it also serves as the first line of defense against inhaled environmental pathogens and toxins. Given these critical roles, disruption of normal cell function or cell-cell interactions can have devastating health consequences. The articles of this Review Series highlight recent progress in understanding the pathophysiology of several pulmonary diseases and suggest how these insights are leading to the development of new therapeutic strategies.
Paul W. Noble
Airspaces of the lung are lined by an epithelium whose cellular composition changes along the proximal-to-distal axis to meet local functional needs for mucociliary clearance, hydration, host defense, and gas exchange. Advances in cell isolation, in vitro culture techniques, and genetic manipulation of animal models have increased our understanding of the development and maintenance of the pulmonary epithelium. This review discusses basic cellular mechanisms that regulate establishment of the conducting airway and gas exchange systems as well as the functional maintenance of the epithelium during postnatal life.
Craig R. Rackley, Barry R. Stripp
The acute respiratory distress syndrome (ARDS) is an important cause of acute respiratory failure that is often associated with multiple organ failure. Several clinical disorders can precipitate ARDS, including pneumonia, sepsis, aspiration of gastric contents, and major trauma. Physiologically, ARDS is characterized by increased permeability pulmonary edema, severe arterial hypoxemia, and impaired carbon dioxide excretion. Based on both experimental and clinical studies, progress has been made in understanding the mechanisms responsible for the pathogenesis and the resolution of lung injury, including the contribution of environmental and genetic factors. Improved survival has been achieved with the use of lung-protective ventilation. Future progress will depend on developing novel therapeutics that can facilitate and enhance lung repair.
Michael A. Matthay, Lorraine B. Ware, Guy A. Zimmerman
Research on the pathogenesis of asthma has traditionally concentrated on environmental stimuli, genetic susceptibilities, adaptive immune responses, and end-organ alterations (particularly in airway mucous cells and smooth muscle) as critical steps leading to disease. The focus of this cascade has been the response to allergic stimuli. An alternative scheme suggests that respiratory viruses and the consequent response of the innate immune system also drives the development of asthma as well as related inflammatory diseases. This conceptual shift raises the possibility that sentinel cells such as airway epithelial cells, DCs, NKT cells, innate lymphoid cells, and macrophages also represent critical components of asthma pathogenesis as well as new targets for therapeutic discovery. A particular challenge will be to understand and balance the innate as well as the adaptive immune responses to defend the host against acute infection as well as chronic inflammatory disease.
Michael J. Holtzman
The current epidemic of chronic obstructive pulmonary disease (COPD) has produced a worldwide health care burden, approaching that imposed by transmittable infectious diseases. COPD is a multidimensional disease, with varied intermediate and clinical phenotypes. This Review discusses the pathogenesis of COPD, with particular focus on emphysema, based on the concept that pulmonary injury involves stages of initiation (by exposure to cigarette smoke, pollutants, and infectious agents), progression, and consolidation. Tissue damage entails complex interactions among oxidative stress, inflammation, extracellular matrix proteolysis, and apoptotic and autophagic cell death. Lung damage by cigarette smoke ultimately leads to self-propagating processes, resulting in macromolecular and structural alterations — features similar to those seen in aging.
Rubin M. Tuder, Irina Petrache
Pulmonary fibrosis occurs in a variety of clinical settings, constitutes a major cause of morbidity and mortality, and represents an enormous unmet medical need. However, the disease is heterogeneous, and the failure to accurately discern between forms of fibrosing lung diseases leads to inaccurate treatments. Pulmonary fibrosis occurring in the context of connective tissue diseases is often characterized by a distinct pattern of tissue pathology and may be amenable to immunosuppressive therapies. In contrast, idiopathic pulmonary fibrosis (IPF) is a progressive and lethal form of fibrosing lung disease that is recalcitrant to therapies that target the immune system. Although animal models of fibrosis imperfectly recapitulate IPF, they have yielded numerous targets for therapeutic intervention. Understanding the heterogeneity of these diseases and elucidating the final common pathways of fibrogenesis are critical for the development of efficacious therapies for severe fibrosing lung diseases.
Paul W. Noble, Christina E. Barkauskas, Dianhua Jiang