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Chronic obstructive pulmonary disease (COPD) is a debilitating lung disease characterised by airflow limitation, chronic bronchitis, emphysema and airway remodelling. Cigarette smoke is considered the primary risk factor for the development of COPD; however, genetic factors, host responses and infection also play an important role. Accumulating evidence highlights a role for iron dyshomeostasis and cellular iron accumulation in the lung as a key contributing factor in the development and pathogenesis of COPD. Recent studies have also shown that mitochondria, the central players in cellular iron utilisation, are dysfunctional in respiratory cells in individuals with COPD, with alterations in mitochondrial bioenergetics and dynamics driving disease progression. Understanding the molecular mechanisms underlying the dysfunction of mitochondria and cellular iron metabolism in the lung may unveil potential novel investigational avenues and therapeutic targets to aid in the treatment of COPD. [ABSTRACT FROM AUTHOR]

Mitochondria are a distinguishing feature of eukaryotic cells. Best known for their critical function in energy production via oxidative phosphorylation (OXPHOS), mitochondria are essential for nutrient and oxygen sensing and for the regulation of critical cellular processes, including cell death and inflammation. Such diverse functional roles for organelles that were once thought to be simple may be attributed to their distinct heteroplasmic genome, exclusive maternal lineage of inheritance, and ability to generate signals to communicate with other cellular organelles. Mitochondria are now thought of as one of the cell's most sophisticated and dynamic responsive sensing systems. Specific signatures of mitochondrial dysfunction that are associated with disease pathogenesis and/or progression are becoming increasingly important. In particular, the centrality of mitochondria in the pathological processes and clinical phenotypes associated with a range of lung diseases is emerging. Understanding the molecular mechanisms regulating the mitochondrial processes of lung cells will help to better define phenotypes and clinical manifestations associated with respiratory disease and to identify potential diagnostic and therapeutic targets. [ABSTRACT FROM AUTHOR]

Significance: Autophagy is a fundamental cellular process that functions in the turnover of subcellular organelles and protein. Activation of autophagy may represent a cellular defense against oxidative stress, or related conditions that cause accumulation of damaged proteins or organelles. Selective forms of autophagy can maintain organelle populations or remove aggregated proteins. Autophagy can increase survival during nutrient deficiency and play a multifunctional role in host defense, by promoting pathogen clearance and modulating innate and adaptive immune responses. Recent Advances: Autophagy has been described as an inducible response to oxidative stress. Once believed to represent a random process, recent studies have defined selective mechanisms for cargo assimilation into autophagosomes. Such mechanisms may provide for protein aggregate detoxification and mitochondrial homeostasis during oxidative stress. Although long studied as a cellular phenomenon, recent advances implicate autophagy as a component of human diseases. Altered autophagy phenotypes have been observed in various human diseases, including lung diseases such as chronic obstructive lung disease, cystic fibrosis, pulmonary hypertension, and idiopathic pulmonary fibrosis. Critical Issues: Although autophagy can represent a pro-survival process, in particular, during nutrient starvation, its role in disease pathogenesis may be multifunctional and complex. The relationship of autophagy to programmed cell death pathways is incompletely defined and varies with model system. Future Directions: Activation or inhibition of autophagy may be used to alter the progression of human diseases. Further resolution of the mechanisms by which autophagy impacts the initiation and progression of diseases may lead to the development of therapeutics specifically targeting this pathway. Antioxid. Redox Signal. 20, 474-494. [ABSTRACT FROM AUTHOR]

The article discusses the evidence emerging for the role of autophagy and selective autophagy in cell survival, cell death, and immune and inflammatory response related to the pathogenesis of complex lung diseases. It discusses the principal components of the autophagic process. The dual nature of autophagy in the lung and the challenge posed by this duality for designing autophagy-based diagnostic and therapeutic targets in lung disease are also examined.

Heme oxygenase (HO), a catabolic enzyme, provides the rate-limiting step in the oxidative breakdown of heme, to generate carbon monoxide (CO), iron, and biliverdin-IXα. Induction of the inducible form, HO-1, in tissues is generally regarded as a protective mechanism. Over the last decade, considerable progress has been made in defining the therapeutic potential of HO-1 in a number of preclinical models of lung tissue injury and disease. Likewise, tissue-protective effects of CO, when applied at low concentration, have been observed in many of these models. Recent studies have expanded this concept to include chemical CO-releasing molecules (CORMs). Collectively, salutary effects of the HO-1/CO system have been demonstrated in lung inflammation/acute lung injury, lung and vascular transplantation, sepsis, and pulmonary hypertension models. The beneficial effects of HO-1/CO are conveyed in part through the inhibition or modulation of inflammatory, apoptotic, and proliferative processes. Recent advances, however, suggest that the regulation of autophagy and the preservation of mitochondrial homeostasis may serve as additional candidate mechanisms. Further preclinical and clinical trials are needed to ascertain the therapeutic potential of HO-1/CO in human clinical disease. [ABSTRACT FROM AUTHOR]