NADPH oxidases in lung health and disease

Abstract

Significance: The evolution of the lungs and circulatory systems in vertebrates ensured the availability of molecular oxygen (O2; dioxygen) for aerobic cellular metabolism of internal organs in large animals. O2 serves as the physiologic terminal acceptor of mitochondrial electron transfer and of the NADPH oxidase (Nox) family of oxidoreductases to generate primarily water and reactive oxygen species (ROS), respectively.

Recent advances: The purposeful generation of ROS by Nox family enzymes suggests important roles in normal physiology and adaptation, most notably in host defense against invading pathogens and in cellular signaling.

Critical issues: However, there is emerging evidence that, in the context of chronic stress and/or aging, Nox enzymes contribute to the pathogenesis of a number of lung diseases.

Future directions: Here, we review evolving functions of Nox enzymes in normal lung physiology and emerging pathophysiologic roles in lung disease.

FIG. 1.

Domain structures and interactions with regulatory subunits in the activation of Nox1 and Nox2. Solid lines represent the known interactions for activation; dashed lines represent inhibitory effects; question marks represent predicted interaction. PX domains of both p47^phox and NoxO1 bind to membrane lipids. AD, activation domain; PR, proline-rich region; PX, phox homology domain; TPR, tetratricopeptide repeat; NOX, NADPH oxidase. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 2.

Cellular localization of Nox enzymes in the lung. Nox/Duox isoforms are expressed in specific lung cells, where they mediate diverse functions in both normal physiologic and/or pathologic states. The catalytic subunits of Nox enzymes are schematically represented by an orange “duplex.” Refer to text for related references and details. ASL, airway surface liquid; Duox, dual oxidase. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 3.

Subcellular localization of Nox enzymes. Nox/Duox isoforms localize to specific subcellular compartments to mediate their cellular functions. The catalytic subunits of Nox enzymes are schematically represented by an orange “duplex.” CEM, caveolin-enriched microdomain; ECM, extracellular matrix; ER, endoplasmic reticulum; H₂O₂, hydrogen peroxide. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 4.

Anatomic localization of Nox enzymes in the lung and associated diseases. Nox/Duox isoforms are expressed in multiple cell types and anatomic locations, extending from the proximal trachea and large airways to terminal bronchioles and alveoli. Proposed associations of Nox/Duox isoforms with specific lung diseases are indicated. ARDS, acute respiratory distress syndrome; COPD, chronic obstructive pulmonary disease. “?” indicates non-identified Nox and/or nox subunits.