Multiple roles of phospholipase A2 during lung infection and inflammation.

Inflammation of the lung marked by excessive recruitment of neutrophils from circulation to the airway is a common feature among several pathological lung disorders, particularly those involving infection (13, 17, 64, 69, 73, 76). Although neutrophils serve a protective role by targeting and eliminating bacterial invaders, excessive neutrophil recruitment and accumulation can cause overactivity of the nonspecific neutrophil destructive capabilities, resulting in severe host lung tissue damage (127). Inflammation associated with bacterial pneumonia results from direct infection of the upper airway by either gram-positive pathogens, such as Streptococcus pneumoniae, or gram-negative species, such as Pseudomonas aeruginosa (73). P. aeruginosa is also the major pathogen colonizing the airway and resulting in neutrophilic lung destruction occurring in the heritable disease cystic fibrosis (CF) (69). Acute respiratory distress syndrome (ARDS) is marked by an influx of inflammatory cells, largely consisting of neutrophils, resulting in increased permeability of the capillary/alveolar barrier and severely impairing oxygenation (76). Although ARDS is not necessarily associated with infection by a specific pathogen, it is often a consequence of sepsis and frequently associated with nosocomial infections (76). Asthma causes reversible airway obstruction involving an aberrantly regulated inflammatory response (64). Eosinophils are the effector immune cells during the asthmatic process and allergens more so than infectious organisms serve as the trigger for an asthmatic attack (64). Severe asthmatic attacks can be exacerbated by respiratory infections, and the pathological process in these severe attacks involves a significant neutrophil presence (13). Chronic obstructive pulmonary disease (COPD) results in airway obstruction that is not fully reversible and is generally brought on by environmental exposure to pollutants, such as cigarette smoke and asbestos (111). Inflammation and airway remodeling are key features in the progression of COPD (13). Since inflammation is a key common component characterizing the pathology of many clinically distinct lung diseases, understanding the mechanisms governing the inflammatory process in the lung may reveal versatile treatment options that could have a beneficial impact on multiple lung disorders. It has become increasingly appreciated over the past couple of decades that the enzyme phospholipase A2 (PLA2) is an important factor in lung diseases that involve inflammation (106). The defining enzymatic function of PLA2 is the cleavage of membrane phospholipids into smaller bioactive molecules that can then participate in a plethora of cellular processes (Fig. ​(Fig.1).1). Determining the particular role of PLA2 in the setting of lung inflammation has proven quite challenging, because this enzyme represents a family of over 20 distinct proteins with various structural and biochemical characteristics (106). For the purposes of this review, the PLA2 enzymes are segregated into six major classes based on biochemical properties: secretory PLA2s (sPLA2s), cytoplasmic PLA2s (cPLA2s), calcium-independent PLA2s (iPLA2s), lysosomal PLA2s, platelet-activating factor acetylhydrolases (PAF-AHs), and PLA2s of bacterial origin (Table ​(Table1).1). PLA2 isoforms representing each of these major groups have been reported to contribute to either the promotion or the resolution of inflammation occurring in the lung during various disease processes (106). A unifying principle for the role of PLA2s in lung disease remains elusive owing to the numbers of PLA2 isoforms that are expressed in the lung combined with the multiple and distinct functions attributable to each isoform. These circumstances represent a significant challenge for the design of anti-inflammatory therapeutics based on modulating the PLA2 enzymatic activity. The purposes of this review are to highlight findings of the roles various PLA2s take part in during lung infection and inflammation and to illustrate the importance of PLA2 in lung disease. FIG. 1. Small arrows depict cleavage sites for the enzymes PLA2, PLA1, and LPLA on the membrane phospholipid, PC. Large arrows depict a sequential reaction beginning with PC, which is converted to lysophosphocholine (LPC) and AA by PLA2. Lysophosphocholine is ... TABLE 1. Phospholipase A2s involved in lung diseasea