Bronchoprotective mechanisms for specialized pro-resolving mediators in the resolution of lung inflammation

doi:10.1016/j.mam.2017.04.003

Molecular Aspects of Medicine

Volume 58, December 2017, Pages 44-56

https://doi.org/10.1016/j.mam.2017.04.003 Get rights and content

Abstract

Bronchi are exposed daily to irritants, microbes and allergens as well as extremes of temperature and acid. The airway mucosal epithelium plays a pivotal role as a sentinel, releasing alarmins when danger is encountered. To maintain homeostasis, an elaborate counter-regulatory network of signals and cellular effector mechanisms are needed. Specialized pro-resolving mediators (SPMs) are chemical mediators that enact resolution programs in response to injury, infection or allergy. SPMs are enzymatically derived from essential polyunsaturated fatty acids with potent cell-type specific immunoresolvent properties. SPMs signal by engaging cell-based receptors to turn off acute inflammatory responses and restore tissue homeostasis. Several common lung diseases involving the airways, including asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis (CF), are characterized by unresolved bronchial inflammation. In preclinical murine models of lung disease, SPMs carry potent bronchoprotective actions. Here, we review cellular and molecular effects for SPM-initiated catabasis in the lung and their human translation.

Introduction

Inflammation is the body's response to injury or infection and manifests clinically as fever and in the lung as cough, sputum production, dyspnea and edema. Biologically, the initiation of acute inflammation results from a highly coordinated network of cellular and molecular events. Pro-inflammatory cytokines and chemokines and eicosanoids including leukotrienes and prostaglandins create a beacon of chemoattractants that results in leukocyte trafficking to sites of lung infection or injury. Endothelial and epithelial barriers become compromised by the inflammatory response creating tissue edema and purulent exudate (expectorated as sputum). Recruited granulocytes and lymphocytes then augment innate tissue-resident leukocytes and macrophages to contain and rid the body of the insult or invading pathogen. Initiating acute inflammation is vital for host protection and survival with many examples of immunosuppression increasing susceptibility to excess morbidity and mortality from infection. Equally important to health is the timely resolution of acute lung inflammation.

To counter the complexity and amplitude of pro-phlogistic mechanisms there exists endogenous resolution programs that are spatio-temporally regulated in the lung. Resolution is an active process designed to restore host tissues to a baseline non-inflamed state, a process termed catabasis. Inflammation resolution is orchestrated by several classes of mediators, including peptides, gases and lipids. Of particular relevance to this review is a superfamily of lipid mediators that are enzymatically-derived from dietary essential polyunsaturated fatty acids (PUFA). These specialized pro-resolving mediators (SPMs) include the arachidonic acid-derived lipoxins and the omega-3 fatty acid-derived resolvins, protectins, and maresins (reviewed in Serhan, 2014). Each of the SPMs are stereoselective with structure activity relationships consistent with agonist properties at cognate receptors. During acute inflammation, lipid mediator class switching occurs as PUFA metabolism switches from pro-inflammatory mediators (e.g., prostaglandins, leukotrienes) to pro-resolving mediators (i.e., SPMs) (Levy et al., 2001). SPMs have cell-type specific and potent immunoresolvent actions to quench pro-inflammatory cytokine production by airway epithelial cells, increase epithelial production of anti-microbial peptides, halt leukocyte trafficking, and promote clearance of the inflammatory leukocytes through natural killer cell-mediated leukocyte apoptosis and macrophage phagocytosis of apoptotic leukocytes (Levy and Serhan, 2014). Thus, in health, SPMs promote the timely resolution of inflammation.

Chronic inflammation results from a failure of the body's resolution pathways to adequately turn off acute inflammatory responses and switch on mechanisms to restore homeostasis. Chronic unresolved inflammation underlies the pathophysiology of several common human lung diseases including asthma, chronic obstructive pulmonary syndrome (COPD), and cystic fibrosis (CF). Active research in humans and pre-clinical animal models of these diseases has uncovered a deficiency of SPMs and their tissue protective pro-resolving actions. Here, we review SPMs molecular, cellular, and biochemical bronchoprotective actions in response to acute inflammation of injury, infection and allergy with human translation in health and, when defective, in airway diseases.

Section snippets

SPM bronchial epithelial actions

The airway mucosa is a first line of host defense against inhaled irritants, allergens, and pathogens. The epithelium provides a physical barrier against inhaled pathogens and toxins and initiates host immune responses through production of alarmins, inflammatory chemokines and cytokines that signal to cellular members of the innate and adaptive immune system. Epithelial cells are targets for regulation by SPMs that act to attenuate pro-inflammatory responses and promote epithelial restitution.

Pre-clinical models of lung disease

Pre-clinical models of lung diseases have consistently uncovered potent immunomodulatory roles for SPMs. Essential PUFAs regulate the host inflammatory response to acute infection and injury through their conversion to bioactive lipid-derived mediators (Samuelsson et al., 1987). In response to tissue injury or infection, arachidonic acid (AA; C20:4n-6), docosahexaenoic acid (DHA; C22:6n-3) and eicosapentaenoic acid (EPA; C20:5n-3) are rapidly released from cellular phospholipids via

Human translation

SPMs are detectable in numerous human body fluids and tissues including peripheral blood, plasma and serum, bronchoalveolar lavage fluid and sputum, cerebrospinal fluid, breast milk, synovial joint fluid, and tears (Serhan, 2014). The levels of lipoxins, resolvins, and protectins in healthy human serum are in the picomolar to nanomolar range (Psychogios et al., 2011) and dietary supplementation with omega-3 fatty acids can increase serum SPM levels (Colas et al., 2014, Mas et al., 2012,

Conclusions

In health, the host airway immune response to invading pathogens, injury, allergen or other noxious stimuli is a spatiotemporally regulated network of cellular and molecular pathways whereby acute inflammatory responses are activated and once the threat is contained, an equally sophisticated resolution pathway is engaged to turn off inflammation for catabasis. With their anti-inflammatory and pro-resolving actions, the PUFA-derived endogenous SPMs are central to the body's counter-regulatory

Disclosure statement

BDL is a co-inventor on patents assigned to Brigham and Women's Hospital. The interests of BDL were reviewed and are managed by the Brigham and Women's Hospital and Partners HealthCare in accordance with their conflict-of-interest policies. MGD and TRB have no pertinent interests to disclose.

Acknowledgements

This work was funded in part by National Institutes of Health Grants R01-HL122531, U01-HL108712, U10-HL109172, U24-AI118656, P01-GM095467 (BDL), and K12-HD047349 (MGD) and by the Sao Paulo Research Foundation (FAPESP) grant 2015/26048-5 (TRB).

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Bronchoprotective mechanisms for specialized pro-resolving mediators in the resolution of lung inflammation

Abstract

Introduction

Section snippets

SPM bronchial epithelial actions

Pre-clinical models of lung disease

Human translation

Conclusions

Disclosure statement

Acknowledgements

Biochem. Biophys. Res. Commun.

Mucosal Immunol.

Am. J. Pathol.

J. Cystic fibrosis: Official J. Eur. Cyst. Fibros. Soc.

Am. J. Pathol.

Chem. Biol.

Mucosal Immunol.

J. Biol. Chem.

Mucosal Immunol.

J. allergy Clin. Immunol.

Am. J. Pathol.

J. Biol. Chem.

Prostagl. Leukot. Essent. Fat. acids

Cell

Blood

Lancet

Prostagl. Leukot. Essent. Fat. acids

Mucosal Immunol.

Maresin 1 biosynthesis during platelet-neutrophil interactions is organ-protective

Proc. Natl. Acad. Sci. U. S. A.

Aspirin-triggered resolvin D1 is produced during self-resolving gram-negative bacterial pneumonia and regulates host immune responses for the resolution of lung inflammation

Mucosal Immunol.

Status of childhood asthma in the United States, 1980-2007

Pediatrics

Resolvin E1 selectively interacts with leukotriene B4 receptor BLT1 and ChemR23 to regulate inflammation

J. Immunol.

Lipoxin A4 regulates natural killer cell and type 2 innate lymphoid cell activation in asthma

Sci. Transl. Med.

Recent advances in understanding and treating ARDS

F1000Res

Corticosteroid suppression of lipoxin A4 and leukotriene B4 from alveolar macrophages in severe asthma

Respir. Res.

Fish oil-derived fatty acids in pregnancy and wheeze and asthma in offspring

N. Engl. J. Med.

ChemR23 dampens lung inflammation and enhances anti-viral immunity in a mouse model of acute viral pneumonia

PLoS Pathog.

Serum amyloid A opposes lipoxin A(4) to mediate glucocorticoid refractory lung inflammation in chronic obstructive pulmonary disease

Proc. Natl. Acad. Sci. U. S. A.

Resolvin E1 promotes mucosal surface clearance of neutrophils: a new paradigm for inflammatory resolution

FASEB J. Official Publ. Fed. Am. Soc. Exp. Biol.

Resolvin E1-induced intestinal alkaline phosphatase promotes resolution of inflammation through LPS detoxification

Proc. Natl. Acad. Sci. U. S. A.

Lipid mediator-induced expression of bactericidal/permeability-increasing protein (BPI) in human mucosal epithelia

Proc. Natl. Acad. Sci.

Chemerin15 inhibits neutrophil-mediated vascular inflammation and myocardial ischemia-reperfusion injury through ChemR23

EMBO Rep.

Synthetic chemerin-derived peptides suppress inflammation through ChemR23

J. Exp. Med.

Lipoxin A4 levels in asthma: relation with disease severity and aspirin sensitivity

Clin. Exp. allergy J. Br. Soc. Allergy Clin. Immunol.

Identification of resolvin D2 receptor mediating resolution of infections and organ protection

J. Exp. Med.

Infection regulates pro-resolving mediators that lower antibiotic requirements

Nature

The lipoxin receptor ALX: potent ligand-specific and stereoselective actions in vivo

Pharmacol. Rev.

The effects of lipoxin A4 on airway responses in asthmatic subjects

Am. Rev. Respir. Dis.

Lethal dissemination of H5N1 influenza virus is associated with dysregulation of inflammation and lipoxin signaling in a mouse model of infection

J. Virol.

Identification and signature profiles for pro-resolving and inflammatory lipid mediators in human tissue. American journal of physiology

Cell physiol.

Lipoxin A4 modulates transmigration of human neutrophils across intestinal epithelial monolayers

J. Clin. Investig.

Ligand-specific conformational change of the G-protein-coupled receptor ALX/FPR2 determines proresolving functional responses

Proc. Natl. Acad. Sci. U. S. A.

Resolvins attenuate inflammation and promote resolution in cigarette smoke-exposed human macrophages

Am. J. Physiol. Lung Cell Mol. Physiol.

Actions of lipoxin A4 and related compounds in smooth muscle preparations and on the microcirculation in vivo

Adv. Exp. Med. Biol.