The article by Yao and coworkers in this issue (Am. J. Respir. Cell Mol. Biol. 2008;39:7–18) reveals that the cyclin-dependent kinase inhibitor p21CIP1/WAF1/SDI1 (designated hereafter as p21), which has been linked to cell cycle growth arrest due to stress or danger cell responses, may modulate alveolar inflammation and alveolar destruction, and thus enlightens our present understanding of how the lung senses injury due to cigarette smoke and integrates these responses with those that activate inflammatory pathways potentially harmful to the lung (1). Furthermore, the interplay of p21 and cellular processes involving cell senescence and the imbalance of cell proliferation/apoptosis may provide us with a more logical explanation of how p21, acting as a sensor of cellular stress, might have such potent and wide roles in lung responses triggered by cigarette smoke. Molecular switches, ontologically designed for the protection of the host, are now hijacked by injurious stresses (such as cigarette smoke), leading to organ damage.
Current therapy for cystic fibrosis (CF) focuses on minimizing the microbial community and the host’s immune response through the aggressive use of airway clearance techniques, broad-spectrum antibiotics, and treatments that break down the pervasive endobronchial biofilm. Antibiotic selection is typically based on the susceptibility of individual microbial strains to specific antibiotics in vitro. Often this approach cannot accurately predict medical outcomes because of factors both technical and biological. Recent culture-independent assessments of the airway microbial and viral communities demonstrated that the CF airway infection is considerably more complex and dynamic than previously appreciated. Understanding the ecological and evolutionary pressures that shape these communities is critically important for the optimal use of current therapies (in both the choice of therapy and timing of administration) and the development of newer strategies. The climax–attack model (CAM) presented here, grounded in basic ecological principles, postulates the existence of two major functional communities. The attack community consists of transient viral and microbial populations that induce strong innate immune responses. The resultant intense immune response creates microenvironments that facilitate the establishment of a climax community that is slower-growing and inherently resistant to antibiotic therapy. Newer methodologies, including sequence-based metagenomic analysis, can track not only the taxonomic composition but also the metabolic capabilities of these changing viral and microbial communities over time. Collecting this information for CF airways will enable the mathematical modeling of microbial community dynamics during disease progression. The resultant understanding of airway communities and their effects on lung physiology will facilitate the optimization of CF therapies.
cystic fibrosis; airway ecology; metagenomics
Autophagy is a homeostatic process common to all eukaryotic cells that serves to degrade intracellular components. Among three classes of autophagy, macroautophagy is best understood, and is the subject of this Review. The function of autophagy is multifaceted, and includes removal of long-lived proteins and damaged or unneeded organelles, recycling of intracellular components for nutrients, and defense against pathogens. This process has been extensively studied in yeast, and understanding of its functional significance in human disease is also increasing. This Review explores the basic machinery and regulation of autophagy in mammalian systems, methods employed to measure autophagic activity, and then focuses on recent discoveries about the functional significance of autophagy in respiratory diseases, including chronic obstructive pulmonary disease, cystic fibrosis, tuberculosis, idiopathic pulmonary fibrosis, pulmonary arterial hypertension, acute lung injury, and lymphangioleiomyomatosis.
autophagy; chronic obstructive pulmonary disease; idiopathic pulmonary fibrosis; epithelial cells; fibroblasts
Acute lung injury (ALI) is a syndrome marked by increased permeability across the pulmonary epithelium resulting in pulmonary edema. Recent evidence suggests that members of the human epidermal growth factor receptor (HER) family are activated in alveolar epithelial cells during ALI and regulate alveolar epithelial barrier function. These tyrosine kinase receptors, which also participate in the pathophysiology of pulmonary epithelial malignancies, regulate cell growth, differentiation, and migration as well as cell–cell adhesion, all processes that influence epithelial injury and repair. In this review we outline mechanisms of epithelial injury and repair in ALI, activation patterns of this receptor family in pulmonary epithelial cells as a consequence injury, how receptor activation alters alveolar permeability, and the possible intracellular signaling pathways involved. Finally, we propose a theoretical model for how HER-mediated modulation of alveolar permeability might affect lung injury and repair. Understanding how these receptors signal has direct therapeutic implications in lung injury and other diseases characterized by altered epithelial barrier function.
acute lung injury; human epidermal growth factor receptor; inflammation; alveolar epithelial cell
Acute lung injury (ALI) is due to an uncontrolled systemic inflammatory response resulting from direct injury to the lung or indirect injury in the setting of a systemic process. Such insults lead to the systemic inflammatory response syndrome (SIRS), which includes activation of leukocytes—alveolar macrophages and sequestered neutrophils—in the lung. Although systemic inflammatory response syndrome is a physiologic response to an insult, systemic leukocyte activation, if excessive, can lead to end organ injury, such as ALI. Excessive recruitment of leukocytes is critical to the pathogenesis of ALI, and the magnitude and duration of the inflammatory process may ultimately determine the outcome in patients with ALI. Leukocyte recruitment is a well orchestrated process that depends on the function of chemokines and their receptors. Understanding the mechanisms that contribute to leukocyte recruitment in ALI may ultimately lead to the development of effective therapeutic strategies.
acute lung injury; inflammation; leukocytes; experimental; clinical
In this review, we examine how a subset of signal transduction cascades initiated by Mycobacterium tuberculosis (Mtb) infection modulates transcription mediated by the human immunodeficiency virus type 1 long terminal repeat (HIV-1 LTR). We describe two distinct phases of signaling that target transcription factors known to bind the HIV-1 LTR, and thus drive viral transcription and replication, in cells of the Mtb-infected host. First, Mtb-derived molecules, including cell wall components and DNA, interact with a number of host pattern recognition receptors. Second, cytokines and chemokines secreted in response to Mtb infection initiate signal transduction cascades through their cognate receptors. Given the variation in cell wall components among distinct clinical Mtb strains, the initial pattern recognition receptor interaction leading to direct LTR activation and differential cytokine and chemokine production is likely to be an important aspect of Mtb strain-specific regulation of HIV-1 transcription and replication. Improved understanding of these molecular mechanisms in the context of bacterial and host genetics should provide key insights into the accelerated viral replication and disease progression characteristic of HIV/TB coinfection.
HIV/TB coinfection; transcription; signal transduction; innate immunity; cytokines
Despite its recognition as a distinct granulomatous disease for over a century, the etiology of sarcoidosis remains to be defined. Since the early 1900s, infectious agents have been suspected in causing sarcoidosis. For much of this time, mycobacteria were considered a likely culprit, yet until recently, the supporting evidence has been tenuous at best. In this review, we evaluate the reported association between mycobacteria and sarcoidosis. Historically, mycobacterial infection has been investigated using histologic stains, cultures of lesional tissue or blood, and identification of bacterial nucleic acids or bacterial antigens. More recently, advances in biochemical, molecular, and immunological methods have produced a more rigorous analysis of the antigenic drivers of sarcoidosis. The result of these efforts indicates that mycobacterial products likely play a role in at least a subset of sarcoidosis cases. This information, coupled with a better understanding of genetic susceptibility to this complex disease, has therapeutic implications.
sarcoidosis; mycobacteria; granulomas; microorganisms; peptides; immune response
cell adhesion; airway epithelia; tight junction; adherens proteins; hemi-desmosomes
Prostaglandin (PG)E2 is a bioactive eicosanoid that regulates many biologically important processes in part due to its ability to signal through four distinct G-protein–coupled receptors with differential signaling activity and unique expression patterns in different cell types. Although PGE2 has been linked to malignancy in many organs, it is believed to play a beneficial role in the setting of fibrotic lung disease. This is in part due to the ability of PGE2 to limit many of the pathobiologic features of lung fibroblasts and myofibroblasts, including the ability of PGE2 to limit fibroblast proliferation, migration, collagen secretion, and, as originally reported in the Journal by us in 2003, the ability to limit transforming growth factor (TGF)-β–induced myofibroblast differentiation. In the setting of lung fibrosis, PGE2 production and signaling is often diminished. In the last 8 years, significant advances have been made to better understand the dysregulation of PGE2 production and signaling in the setting of lung fibrosis. We also have a clearer picture of how PGE2 inhibits myofibroblast differentiation and the receptor signaling pathways that can influence fibroblast proliferation. This review highlights these recent advances and offers new insights into the potential ways that PGE2 and its downstream signals can be regulated for therapeutic benefit in a disease that has no validated treatment options.
PGE2; myofibroblasts; collagen; lung; epigenetics
Vascular remodeling is an important pathological feature of pulmonary arterial hypertension (PAH), which leads to increased pulmonary vascular resistance, with marked proliferation of pulmonary artery smooth muscle cells (SMC) and/or endothelial cells (EC). Successful treatment of experimental PAH with a platelet-derived growth factor (PDGF) receptor tyrosine kinase inhibitor offers the perspective of “reverse remodeling” (i.e., the regression of established pulmonary vascular lesions). Here we ask the question: which forms of pulmonary vascular remodeling are reversible and can such remodeling caused by angiogenic proliferation of EC be reversed? It is important to emphasize that the report showing reduction of vascular remodeling by PDGF receptor tyrosine kinase inhibitor showed only a reduction of the pulmonary artery muscularization in chronic hypoxia and monocrotaline models, which lack the feature of clustered proliferated EC in the lumen of pulmonary arteries. The regression of vascular muscularization is an important manifestation, whereby proliferative adult SMC convert back to a nonproliferative state. In contrast, in vitro experiments assessing the contribution of EC to the development of PAH demonstrated that phenotypically altered EC generated as a consequence of a vascular endothelial growth factor receptor blockade did not reverse to normal EC. Whereas it is suggested that the proliferative state of SMC may be reversible, it remains unknown whether phenotypically altered EC can switch back to a normal monolayer-forming EC. This article reviews the pathogenetic concepts of severe PAH and explains the many forms in PAH with reversible or irreversible remodeling.
remodeling; PAH; endothelial cell; smooth muscle cell
Bacterial lung diseases are a major cause of morbidity and mortality both in immunocompromised and in immunocompetent individuals. Neutrophil accumulation, a pathological hallmark of bacterial diseases, is critical to host defense, but may also cause acute lung injury/acute respiratory distress syndrome. Toll-like receptors, nucleotide-binding oligomerization domain (NOD)-like receptors, transcription factors, cytokines, and chemokines play essential roles in neutrophil sequestration in the lungs. This review highlights our current understanding of the role of these molecules in the lungs during bacterial infection and their therapeutic potential. We also discuss emerging data on cholesterol and ethanol as environmentally modifiable factors that may impact neutrophil-mediated pulmonary innate host defense. Understanding the precise molecular mechanisms leading to neutrophil influx in the lungs during bacterial infection is critical for the development of more effective therapeutic and prophylactic strategies to control the excessive host response to infection.
bacterial pneumonia; lung inflammation; acute lung injury
Regulatory T cells (Tregs) play an essential role in maintaining the homeostatic balance of immune responses. Asthma is an inflammatory condition of the airways that is driven by dysregulated immune responses toward normally innocuous antigens. Individuals with asthma have fewer and less functional Tregs, which may lead to uncontrolled effector cell responses and promote proasthmatic responses of T helper type 2, T helper 17, natural killer T, antigen-presenting, and B cells. Tregs have the capacity to either directly or indirectly suppress these responses. Hence, the induced expansion of functional Tregs in predisposed or individuals with asthma is a potential approach for the prevention and treatment of asthma. Infection by a number of micro-organisms has been associated with reduced prevalence of asthma, and many infectious agents have been shown to induce Tregs and reduce allergic airways disease in mouse models. The translation of the regulatory and therapeutic properties of infectious agents for use in asthma requires the identification of key modulatory components and the development and trial of effective immunoregulatory therapies. Further translational and clinical research is required for the induction of Tregs to be harnessed as a therapeutic strategy for asthma.
asthma; regulatory T cell; forkhead box p3; immunoregulatory therapy
Mucous cell metaplasia is induced in response to harmful insults and provides front-line protection to clear the airway of toxic substances and cellular debris. In chronic airway diseases mucous metaplasia persists and results in airway obstruction and contributes significantly to morbidity and mortality. Mucus hypersecretion involves increased expression of mucin genes, and increased mucin production and release. The past decade has seen significant advances in our understanding of the molecular mechanisms by which these events occur. Inflammation stimulates epidermal growth factor receptor activation and IL-13 to induce both Clara and ciliated cells to transition into goblet cells through the coordinated actions of FoxA2, TTF-1, SPDEF, and GABAAR. Ultimately, these steps lead to up-regulation of MUC5AC expression, and increased mucin in goblet cell granules that fuse to the plasma membrane through actions of MARCKS, SNAREs, and Munc proteins. Blockade of mucus in exacerbations of asthma and chronic obstructive pulmonary disease may affect morbidity. Development of new therapies to target mucus production and secretion are now possible given the advances in our understanding of molecular mechanisms of mucous metaplasia. We now have a greater incentive to focus on inhibition of mucus as a therapy for chronic airway diseases.
mucus; goblet cell; airway epithelium; asthma; COPD
Sarcoidosis is a noncaseating granulomatous disease, likely of autoimmune etiology, that causes inflammation and tissue damage in multiple organs, most commonly the lung, but also skin, and lymph nodes. Reduced dendritic cell (DC) function in sarcoidosis peripheral blood compared with peripheral blood from control subjects suggests that blunted end organ cellular immunity may contribute to sarcoidosis pathogenesis. Successful treatment of sarcoidosis with tumor necrosis factor (TNF) inhibitors, which modulate DC maturation and migration, has also been reported. Together, these observations suggest that DCs may be important mediators of sarcoidosis immunology. This review focuses on the phenotype and function of DCs in the lung, skin, blood, and lymph node of patients with sarcoidosis. We conclude that DCs in end organs are phenotypically and functionally immature (anergic), while DCs in the lymph node are mature and polarize pathogenic Th1 T cells. The success of TNF inhibitors is thus likely secondary to inhibition of DC-mediated Th1 polarization in the lymph node.
sarcoidosis; granuloma; dendritic cell; macrophage; inflammation
The primary function of neutrophils in host defense is to contain and eradicate invading microbial pathogens. This is achieved through a series of swift and highly coordinated responses culminating in ingestion (phagocytosis) and killing of invading microbes. While these tasks are usually performed without injury to host tissues, in pathologic circumstances such as sepsis, potent antimicrobial compounds can be released extracellularly, inducing a spectrum of responses in host cells ranging from activation to injury and death. In the lung, such inflammatory damage is believed to contribute to the pathogenesis of diverse lung diseases, including acute lung injury and the acute respiratory distress syndrome, chronic obstructive lung disease, and cystic fibrosis. In these disorders, epithelial cells are targets of leukocyte-derived antimicrobial products, including proteinases and oxidants. Herein, we review the mechanisms involved in the physiologic process of neutrophil transepithelial migration, including the role of specific adhesion molecules on the leukocyte and epithelial cells. We examine the responses of the epithelial cells to the itinerant leukocytes and their cytotoxic products and the consequences of this for lung injury and repair. This paradigm has important clinical implications because of the potential for selective blockade of these pathways to prevent or attenuate lung injury.
inflammation; acute lung injury; tight junctions; adherens junctions; proteolytic enzymes
Platelets are the chief effector cells in hemostasis and have additional major functions in inflammation, vascular integrity, and tissue repair. Platelets and the lungs have interrelated activities. Previous studies provide evidence that platelets contribute to pulmonary vascular barrier function and are required for defense against pulmonary hemorrhage, and that the lungs can influence platelet number and distribution. There is also evidence that platelets contribute to pathologic syndromes of pulmonary inflammation and thrombosis. Thus, platelets have an “amicus or adversary” relationship with the lung. Recent observations and discoveries have established new paradigms relevant to influences of platelets on lung cell and molecular biology. These new findings are in a variety of areas including thrombopoieis, nontraditional activities of platelets, new synthetic capabilities and mechanisms of post-translational gene expression, interactions of platelets with endothelial cells and contributions to alveolar capillary barrier permeability, interactions of platelets with myeloid leukocytes, and platelet involvement in stem cell signaling and vascular repair. These issues are considered in a translational approach, with an emphasis on acute lung injury and the acute respiratory distress syndrome.
platelets; inflammation; thrombosis; lung injury
MUC1 is a membrane-tethered mucin expressed on the surface of epithelial cells lining mucosal surfaces. Recent studies have begun to elucidate the physiologic function of MUC1 in the airways, pointing to an antiinflammatory role that is initiated late in the course of bacterial infection and is mediated through inhibition of TLR signaling. These new findings have great potential for clinical applications in controlling excessive and prolonged lung inflammation. This review briefly summarizes the protein structural features of MUC1 relevant to its function, the discovery of its antiinflammatory properties, and potential directions for future avenues of study.
MUC1 mucin; antiinflammatory; airway infection
Elimination of activated inflammatory cells that infiltrate and damage host organs can reduce morbidity and mortality. A better understanding of the mechanisms by which these processes occur may lead to new approaches to prevent tissue damage. The lungs, gastrointestinal tract, and skin are particularly prone to infection and collateral damage by inflammatory cells. Specialized lymphocytes protect these organs from collateral tissue damage by eliminating neutrophils and macrophages from inflamed tissues. These lymphocytes recognize signals produced by inflammatory cells. One such signal is heat shock protein (Hsp) expressed on the cell surface of inflamed phagocytes. Mammalian Hsp molecules closely resemble their microbial equivalents, and therefore phagocytes decorated with these molecules are recognized as target cells. T lymphocytes bearing the γδ T cell receptor (TCR) elicit cytotoxic activity toward macrophages and neutrophils that express Hsp60 and Hsp70, respectively, protecting host organs from collateral tissue damage by phagocytes.
γδTCR; macrophages; neutrophils; inflammatory tissue damage; immunoregulation
Cyclic adenosine monophosphate (cAMP) was the original “second messenger” to be discovered. Its formation is promoted by adenylyl cyclase activation after ligation of G protein–coupled receptors by ligands including hormones, autocoids, prostaglandins, and pharmacologic agents. Increases in intracellular cAMP generally suppress innate immune functions, including inflammatory mediator generation and the phagocytosis and killing of microbes. The importance of the host cAMP axis in regulating antimicrobial defense is underscored by the fact that microbes have evolved virulence-enhancing strategies that exploit it. Many clinical situations that predispose to infection are associated with increases in cAMP, and therapeutic strategies to interrupt cAMP generation or actions have immunostimulatory potential. This article reviews the anatomy of the cAMP axis, the mechanisms by which it controls phagocyte immune function, microbial strategies to dysregulate it, and its clinical relevance.
phagocytes; host defense; G protein–coupled receptors; protein kinase A; exchange protein activated by cyclic AMP
β2-adrenergic receptors are present throughout the lung, including the alveolar airspace, where they play an important role for regulation of the active Na+ transport needed for clearance of excess fluid out of alveolar airspace. β2-adrenergic receptor signaling is required for up-regulation of alveolar epithelial active ion transport in the setting of excess alveolar edema. The positive, protective effects of β2-adrenergic receptor signaling on alveolar active Na+ transport in normal and injured lungs provide substantial support for the use of β-adrenergic agonists to accelerate alveolar fluid clearance in patients with cardiogenic and noncardiogenic pulmonary edema. In this review, we summarize the role of β2-adrenergic receptors in the alveolar epithelium with emphasis on their role in the regulation of alveolar active Na+ transport in normal and injured lungs.
pulmonary edema; acute respiratory distress syndrome; acute lung injury; alveoli; albuterol
Discussions of the initiation of pulmonary arterial hypertension (PAH) in man and in experimental models have centered around intimal and medial proliferation in medium-sized pulmonary arteries. The histologic events are thought to include disordered proliferation of enlarged, vacuolated endothelial cells, neo-muscularization of the affected blood vessels, and vascular pruning. The discovery of the association of familial and sporadic PAH with mutations in BMPR2 has generated intense interest in cytokine receptor trafficking and function in the endothelial cell and how this might be disrupted to yield an enlarged proliferative cell phenotype. Nevertheless, considerations of the subcellular machinery of membrane trafficking in the endothelial cell and consequences of the disruption of this outward and inward membrane trafficking are largely absent from discussions of the pathobiology of PAH. Long-standing electron microscopy data in the PAH field has demonstrated marked disruptions of intracellular membrane trafficking in human and experimental PAH. Further, a role of the membrane-trafficking regulator Nef in simian HIV-induced PAH in macaques and in HIV-induced PAH in man is now evident. Additionally, monocrotaline and hypoxia are known to disrupt the function of Golgi tethers, SNAREs, SNAPs, and N-ethylmaleimide–sensitive factor (“the Golgi blockade hypothesis”). These results, along with recent reports demonstrating the trapping of PAH-associated human BMPR2 mutants in the Golgi, highlight the implications of disrupted intracellular membrane trafficking in the pathobiology of PAH. The purpose of this review is to present a brief overview of the molecular basis of intracellular trafficking and relate these considerations to the pathobiology of PAH.
pulmonary hypertension; endothelium; Golgi organelle; vesicular trafficking
Lymphangioleiomyomatosis (LAM) is a rare progressive cystic lung disease affecting young women. The pivotal observation that LAM occurs both spontaneously and as part of the tuberous sclerosis complex (TSC) led to the hypothesis that these disorders share common genetic and pathogenetic mechanisms. In this review we describe the evolution of our understanding of the molecular and cellular basis of LAM and TSC, beginning with the discovery of the TSC1 and TSC2 genes and the demonstration of their involvement in sporadic (non-TSC) LAM. This was followed by rapid delineation of the signaling pathways in Drosophila melanogaster with confirmation in mice and humans. This knowledge served as the foundation for novel therapeutic approaches that are currently being used in human clinical trials.
tuberous sclerosis; TSC1; TSC2; mTOR; signal transduction; estrogen
Beryllium (Be)-antigen presentation to Be-specific CD4+ T cells from the lungs of patients with chronic beryllium disease (CBD) results in T cell proliferation and TNF-α secretion. We tested the hypothesis that Be-induced, CBD bronchoalveolar lavage (BAL) T cell, transcription-dependent, TNF-α secretion was accompanied by specific transcription factor upregulation. After 6 h of Be stimulation, CBD BAL cells produced a median of 883 pg/ml TNF-α (range, 608–1,275 pg/ml) versus 198 pg/ml (range, 116–245 pg/ml) by unstimulated cells. After 12 h CBD BAL cells produced a median of 2,963 pg/ml (range, 99–9,424 pg/ml) TNF-α versus 55 pg/ml (range, 0–454) by unstimulated cells. Using real-time RT-PCR, Be-stimulated TNF-α production at 6 h was preceded by a 5-fold increase in TNF-α pre-mRNA copy number:β-actin copy number (Be median ratio 0.21; unstimulated median ratio 0.04). The median ratio of mature TNF-α mRNA:β-actin mRNA was upregulated 1.4-fold (Be median ratio 0.17; unstimulated median ratio 0.12). Be exposure in the presence of the transcription inhibitor pentoxifylline (PTX) decreased CBD BAL cell TNF-α pre-mRNA levels > 60%, whereas treatment with the mRNA splicing inhibitor 2-aminopurine (2AP) decreased levels 40% relative to Be exposure alone. PTX treatment decreased mature TNF-α mRNA levels 50% while 2AP decreased levels > 80%, relative to Be exposure alone. Beryllium exposure specifically upregulated transcription factors AP-1 and NF-κB. The data suggest that Be exposure induces transcription-dependent TNF-α production, potentially due to upregulation of specific transcription factors.
granuloma; T lymphocytes; cytokines; gene regulation; lung
Mucus secretions have played a central role in the evolution of multicellular organisms, enabling adaptation to widely differing environments. In vertebrates, mucus covers and protects the epithelial cells in the respiratory, gastrointestinal, urogenital, visual, and auditory systems, amphibian's epidermis, and the gills in fishes. Deregulation of mucus production and/or composition has important consequences for human health. For example, mucus obstruction of small airways is observed in chronic airway diseases, including chronic obstructive pulmonary disease, asthma, and cystic fibrosis. The major protein component in the mucus is a family of large, disulfide-bonded glycoproteins known as gel-forming mucins. These proteins are accumulated in large, regulated secretory granules (the mucin granules) that occupy most of the apical cytoplasm of specialized cells known as mucous/goblet cells. Since mucin oligomers have contour dimensions larger than the mucin granule average diameter, the question arises how these highly hydrophilic macromolecules are organized within these organelles. I review here the intraluminal organization of the mucin granule in view of our knowledge on the structure, biosynthesis, and biophysical properties of gel-forming mucins, and novel imaging studies in living mucous/goblet cells. The emerging concept is that the mucin granule lumen comprises a partially condensed matrix meshwork embedded in a fluid phase where proteins slowly diffuse.
granule matrix; mucin granules; mucins; secretory granules; secretion
Resolution of acute lung inflammation and injury is an active process; it is not merely the absence of proinflammatory signals. Restoration of homeostasis is coordinated by specific mediators and cellular events. In response to injury and inflammatory stimuli, infiltrating leukocytes and tissue-resident cells interact to generate lipoxins (LXs), which are bioactive eicosanoids derived from arachidonic acid. In contrast to proinflammatory leukotrienes and prostaglandins, LXs display potent antiinflammatory actions. LXA4 interacts with a G protein–coupled receptor, termed ALX, that transduces counter-regulatory signals in part via intracellular polyisoprenyl phosphate remodeling. Presqualene diphosphate (PSDP) is a polyisoprenyl phosphate in human neutrophils that is rapidly converted to presqualene monophosphate (PSMP) upon cell activation. PSDP, but not PSMP, directly inhibits phospholipase D, phosphoinositol-3 kinase, and superoxide anion generation. LXs block PSDP turnover in neutrophil membranes to prevent proinflammatory responses. Hence, LX and polyisoprenyl phosphate signaling provide a counter-regulatory circuit to promote resolution of acute lung inflammation. LXA4 and PSDP mimetics have been prepared with potent protective actions in murine models of asthma and acute lung injury.
acute inflammation; lipid mediators; resolution