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 (ICUs). 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 in order 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 pro-inflammatory and pro-survival 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.

Neutrophil‐endothelial interactions of murine cells is not a good predictor of their interactions in human cells

“…23 However, the underlying pathophysiology of neutrophil-mediated tissue damage is yet to be understood and there are no specific pharmacologic therapies available that protect from neutrophilmediated tissue damage. 24,25 Most in vivo studies of mechanisms of inflammatory disease primarily employ murine models. However, concerns regarding the level of correspondence between mice and cell culture models, as well as phenotypic heterogeneity of different types of endothelial cells, and their relevance to human disease, have been expressed in the literature.…”

Biodistribution and Efficacy of Targeted Pulmonary Delivery of a Protein Kinase C-δ Inhibitory Peptide: Impact on Indirect Lung Injury

“…Protein kinase C-d (PKCd) is activated by mediators involved in the septic response, including endotoxin, tumor necrosis factor, and interleukin-1b (Page et al, 2003;Kilpatrick et al, 2010;Mondrinos et al, 2013), functioning to integrate proinflammatory activities in pulmonary epithelial cells, endothelial cells, macrophages, and circulating leukocytes during acute lung inflammation (Mondrinos et al, 2013). Inflammatory pathologies such as ischemia-reperfusion (Chou et al, 2004) and endotoxin-induced lung injury (Chichger et al, 2012) are attenuated in PKCd 2/2 mice.…”

Reducing the Burden of Acute Respiratory Distress Syndrome

“…sepsis and ARDS) occurs, it seems unlikely that narrow mechanistic intervention trials will work (149, 150). Attempts at de-individualizing care, at the clinician level, have improved survival in sepsis (151).…”