Protein kinase C and acute respiratory distress syndrome

Abstract

The acute respiratory distress syndrome (ARDS) is a major public health problem and a leading source of morbidity in intensive care units. Lung tissue in patients with ARDS is characterized by inflammation, with exuberant neutrophil infiltration, activation, and degranulation that is thought to initiate tissue injury through the release of proteases and oxygen radicals. Treatment of ARDS is supportive primarily because the underlying pathophysiology is poorly understood. This gap in knowledge must be addressed to identify urgently needed therapies. Recent research efforts in anti-inflammatory drug development have focused on identifying common control points in multiple signaling pathways. The protein kinase C (PKC) serine-threonine kinases are master regulators of proinflammatory signaling hubs, making them attractive therapeutic targets. Pharmacological inhibition of broad-spectrum PKC activity and, more importantly, of specific PKC isoforms (as well as deletion of PKCs in mice) exerts protective effects in various experimental models of lung injury. Furthermore, PKC isoforms have been implicated in inflammatory processes that may be involved in the pathophysiologic changes that result in ARDS, including activation of innate immune and endothelial cells, neutrophil trafficking to the lung, regulation of alveolar epithelial barrier functions, and control of neutrophil proinflammatory and prosurvival signaling. This review focuses on the mechanistic involvement of PKC isoforms in the pathogenesis of ARDS and highlights the potential of developing new therapeutic paradigms based on the selective inhibition (or activation) of specific PKC isoforms.

Figure 1

Schematic illustrating some of the major events in the pathogenesis of ARDS. A: Top left panel: Normal alveolus with type I and type II epithelial cells, resident alveolar macrophage, capillary endothelial cells and inactivated circulating neutrophils. B: Top right panel: Activation of the innate immune system by indirect or direct lung injury (PAMPs/DAMPs) results in the release of proinflammatory cytokines and ROS by alveolar macrophages. Lung endothelial and epithelial activation further amplifies expression of cytokines and adhesion molecules that promote neutrophil adhesion and activation. C: Bottom right panel: The proinflammatory cascade drives robust neutrophil migration into a thickened, edematous interstitium and also into the alveolar space. Release of toxic mediators by recruited inflammatory cells drives cell death and lung tissue injury. Loss of epithelial barrier function results in flooding of the alveoli and hyaline membrane formation, thus impairing gas exchange.

Figure 2

Schematic illustrating the structural arrangement of binding sites in the regulatory and catalytic domains of the conventional, novel and atypical PKC subfamilies. The catalytic subunit contains an ATP binding site and substrate binding domains which are largely conserved across isoforms. The regulatory domains are more divergent in terms of both structure and function. Only the classical isoforms contain a calcium binding activation site, while all the subfamilies contain binding sites for activation by DAG (classical and novel) or other phospholipid messengers (atypical). The regulatory domain in each subfamily contains a pseudosubstrate binding sequence that binds and inhibits kinase function in the absence of activating signals.

Figure 3

Targeting of PKC-δ in sepsis-induced lung injury. Selective inhibition of PKC-δ targets multiple control points in the development and early progression of ARDS as outlined in Figure 1. PKC-δ inhibition reduces activation of alveolar macrophages (decreased ROS production), endothelial cells (decreased NFκB activation, cytokine and adhesion molecule expression), and epithelial cells (decreased chemokine/cytokine production, increased survival). Importantly to the pathogenesis of ARDS, PKC-δ inhibition targets several key neutrophil functions including adhesion, migration, ROS production and prolonged (pathological) survival. Through inhibition of multiple arms of the proinflammatory cascade it is possible to protect against lung injury – and perhaps provide new tools for the clinical management of ARDS that address the underlying pathology.