Key mechanisms governing resolution of lung inflammation

Semin Immunopathol Key mechanisms governing resolution of lung inflammation C. T. Robb 0 K. H. Regan 0 D. A. Dorward 0 A. G. Rossi 0 0 MRC Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh Medical School , 47 Little France Crescent, Edinburgh EH16 4TJ , UK Innate immunity normally provides excellent defence against invading microorganisms. Acute inflammation is a form of innate immune defence and represents one of the primary responses to injury, infection and irritation, largely mediated by granulocyte effector cells such as neutrophils and eosinophils. Failure to remove an inflammatory stimulus (often resulting in failed resolution of inflammation) can lead to chronic inflammation resulting in tissue injury caused by high numbers of infiltrating activated granulocytes. Successful resolution of inflammation is dependent upon the removal of these cells. Under normal physiological conditions, apoptosis (programmed cell death) precedes phagocytic recognition and clearance of these cells by, for example, macrophages, dendritic and epithelial cells (a process known as efferocytosis). Inflammation contributes to immune defence within the respiratory mucosa (responsible for gas exchange) because lung epithelia are continuously exposed to a multiplicity of airborne pathogens, allergens and foreign particles. Failure to resolve inflammation within the respiratory mucosa is a major contributor of numerous lung diseases. This review will summarise the major mechanisms regulating lung inflammation, including key cellular interplays such as apoptotic cell clearance by alveolar macrophages and macrophage/neutrophil/epithelial cell interactions. The different acute and chronic inflammatory disease states caused by dysregulated/ impaired resolution of lung inflammation will be discussed. Neutrophils; Eosinophils; Macrophages; Lung inflammation; Lung diseases; Pro-resolution mediators; Apoptosis; ETosis; Efferocytosis - This submission is related to Immunopathology of Lung Diseases - Drs. Tracy Hussel and Aleksander Grabiec Introduction Acute inflammatory responses are initiated by injury, infection and irritation which, in turn, protect the host from systemic infection and help to restore tissue homeostasis [ 1 ]. Inflammation therefore represents a crucial defence mechanism that is protective and vital to health [ 2, 3 ]. Typically, the molecular events and cellular interplays prevalent during acute inflammatory responses are efficient at minimising impending injury, infection or irritation, which leads importantly to restoration of tissue homeostasis and thus complete resolution of the acute inflammatory response. However, if an acute inflammatory response is mounted that is uncontrolled in terms of magnitude or duration, it can lead to disease [ 1, 3 ]. In the lung, dysregulated acute inflammation can result in lung injury contributing to pulmonary fibrosis that severely impairs essential gas exchange processes. Therefore, numerous mechanisms exist, which tightly regulate the gravity and duration of lung inflammation. If unresolved, acute lung injury (ALI) and/ or lung inflammation can progress to chronic inflammation, which occurs in lung diseases such as acute respiratory distress syndrome (ARDS), asthma, cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) [ 1 ]. Pro-resolution of inflammation was previously regarded as a passive process, with limited understanding of mechanisms regulating the resolution of inflammation. However, over the years, substantial research in this field has identified inflammation resolution as an active and highly regulated cellular and biochemical process. It is now known that numerous molecular mediators of inflammation exist, including many proand anti-inflammatory cytokines and chemokines, with attenuation of pro-inflammatory mediator effects assisting in the successful ‘switching off’ of inflammation [ 4 ]. More recently, several endogenous pro-resolving bioactive lipid mediators (immunoresolvents) have been discovered such as lipoxins, resolvins, protectins and maresins, which are heavily involved in driving ‘programmed resolution’ that successfully terminate inflammation [ 5–8 ]. Other key processes governing the successful resolution of inflammation include the phagocytic clearance of apoptotic cells [ 9, 10 ] during a process referred to as efferocytosis that also results in the phagocytic cells, switching phenotype from a pro-inflammatory cell to a more anti-inflammatory/pro-resolution phenotype [ 10, 11 ]. Also, pertinent to the lung mucociliary clearance of infective agents, allergens, foreign particles and effete cells occur [12]. This review encompasses the cellular mechanisms and chief biochemical mediators involved in the resolution of lung inflammation and repair of damaged tissues, with a specific focus on neutrophil/eosinophil-dominant lung inflammation and pharmacological approach (...truncated)