Resolution of acute inflammation in the lung

Abstract

Acute inflammation in the lung is essential to health. So too is its resolution. In response to invading microbes, noxious stimuli, or tissue injury, an acute inflammatory response is mounted to protect the host. To limit inflammation and prevent collateral injury of healthy, uninvolved tissue, the lung orchestrates the formation of specialized proresolving mediators, specifically lipoxins, resolvins, protectins, and maresins. These immunoresolvents are agonists for resolution that interact with specific receptors on leukocytes and structural cells to blunt further inflammation and promote catabasis. This process appears to be defective in several common lung diseases that are characterized by excess or chronic inflammation. Here, we review the molecular and cellular effectors of resolution of acute inflammation in the lung.

Figure 1. SPM promote the resolution of tissue inflammation and limit further leukocyte recruitment

With the initiation of acute inflammation, circulating leukocytes are recruited from the microcirculation to tissues to respond to an invading pathogen, organ injury or a noxious stimulus. To prevent excess inflammation and collateral injury of healthy tissue, there are several mechanisms to restrain the inflammatory response, some of which are illustrated here. With source control, neutrophils (cytokine- or NK cell-induced) and T-cells (activation-induced) undergo apoptosis. SPM increase apoptotic leukocyte expression of CCR5 that serves an important pro-resolving role as a chemokine scavenger. Macrophage efferocytosis of CCR5-expressing apoptotic leukocytes effectively clears the cellular debris and pro-inflammatory chemokines and concomitantly initiates the generation of SPM that also limit further leukocyte recruitment, activation and maturation. These cellular events are pivotal to the termination of acute inflammation.

Figure 2. Anti-inflammation and pro-resolution are not synonymous

In response to allergic inflammation in the lung, SPM display both anti-inflammatory and pro-resolving actions. The terms – anti-inflammatory and pro-resolving – do not have identical meaning. Anti-inflammation can lead to immunosuppression that increases the host’s susceptibility to infection. Pro-resolution enhances host defense, in part by catabasis; returning inflamed tissue to homeostasis. For SPM, anti-inflammatory properties include blocking granulocyte further recruitment and activation, inhibition of T-cell and ILC2 cytokine release, decreasing vascular permeability and dampening reactive oxygen species generation. Pro-resolving activities include stimulating epithelial reconstitution, inducing T-cell apoptosis, increasing NK cell-mediated leukocyte apoptosis, augmenting B cell differentiation and antibody generation, promoting macrophage efferocytosis and phagocytosis, counter-regulating pro-inflammatory mediators and decreasing CNS microglial cell and peripheral sensory neuron activation.

Figure 3. Biosynthesis of specialized pro-resolving mediators (SPM) from polyunsaturated fatty acids

Specialized pro-resolving mediators (SPM) are enzymatically derived from host essential fatty acids, including arachidonic acid (C20:4n-6), eicosapentaenoic acid (C20:5n-3) and docosahexaenoic acid (C22:6n-3). In a lipoxygenase (LOX) dependent manner, these polyunsaturated fatty acids are converted to families of SPM as indicated. SPM are stereoselective and representative structures of family members with the complete stereochemical assignment established are shown. For additional details, see reference (9).

Figure 4. Transcellular biosynthesis of SPM occurs via airway neutrophil-epithelium interactions

Transcellular biosynthesis of SPM provides a collaborative opportunity for two cell types to generate mediators together that neither cell type alone can efficiently produce. For example, arachidonic acid (AA) can be released from cell membranes for conversion by 15-LOX to 15S-HETE that is transferred to neutrophils for subsequent transformation by 5-LOX to an unstable epoxytetraene intermediate that hydrolases can convert to LXA₄ and LXB₄. Depicted as unidirectional, lipoxin biosynthesis can proceed bidirectionally with neutrophil 5-LOX conversion of AA to leukotriene A₄ followed by release and transformation to lipoxins by epithelial 15-LOX. Protectin D1 does not require cell-cell interactions for its generation by 15-LOX catalyzed conversion of DHA via an epoxide-containing intermediate.

Figure 5. Aspirin-triggered biosynthesis of epimer resolvins

Aspirin (ASA) acetylated cyclooxygenase-2 (COX-2) is not catalytically inactive. Rather, aspirin-acetylated COX-2 can convert DHA to 17R-HDHA that can be transferred to leukocytes for subsequent transformation by 5-LOX to 17-epi-resolvins, including 17-epi-RvD1. These aspirin-triggered resolvins are epimers of the 15-LOX-derived 17S D-series resolvins.