Regulation of Neutrophilic Inflammation by Proteinase-Activated Receptor 1 during Bacterial Pulmonary Infection

Abstract

Neutrophils are key effector cells of the innate immune response to pathogenic bacteria, but excessive neutrophilic inflammation can be associated with bystander tissue damage. The mechanisms responsible for neutrophil recruitment to the lungs during bacterial pneumonia are poorly defined. In this study, we focus on the potential role of the major high-affinity thrombin receptor, proteinase-activated receptor 1 (PAR-1), during the development of pneumonia to the common lung pathogen Streptococcus pneumoniae. Our studies demonstrate that neutrophils were indispensable for controlling S. pneumoniae outgrowth but contributed to alveolar barrier disruption. We further report that intra-alveolar coagulation (bronchoalveolar lavage fluid thrombin–antithrombin complex levels) and PAR-1 immunostaining were increased in this model of bacterial lung infection. Functional studies using the most clinically advanced PAR-1 antagonist, SCH530348, revealed a key contribution for PAR-1 signaling in influencing neutrophil recruitment to lung airspaces in response to both an invasive and noninvasive strain of S. pneumoniae (D39 and EF3030) but that PAR-1 antagonism did not impair the ability of the host to control bacterial outgrowth. PAR-1 antagonist treatment significantly decreased pulmonary levels of IL-1β, CXCL1, CCL2, and CCL7 and attenuated alveolar leak. Ab neutralization studies further demonstrated a nonredundant role for IL-1β, CXCL1, and CCL7 in mediating neutrophil recruitment in response to S. pneumoniae infection. Taken together, these data demonstrate a key role for PAR-1 during S. pneumoniae lung infection that is mediated, at least in part, by influencing multiple downstream inflammatory mediators.

The pulmonary endothelium in acute respiratory distress syndrome: insights and therapeutic opportunities

“…These negative trial data may temper enthusiasm for ongoing research in this area. Nonetheless, PAR-1 antagonism has recently shown beneficial effects on neutrophil migration, cytokine release and barrier disruption in a murine pneumonia model160 suggesting that alternative targets in the pathway may hold therapeutic promise.…”

What drives neutrophils to the alveoli in ARDS?

“…After challenge with lipopolysaccharide (LPS) or live bacteria, CCL2 and CCL7 were rapidly upregulated in the lungs, the CC chemokine receptors CCR1 and CCR2 were expressed on neutrophils, and blockade of CCL2 and/or CCL7 attenuated neutrophil recruitment 17 18…”

“…In addition, the cellular sources of CCL2 and CCL7 and the mechanisms that induce their synthesis are not completely understood. Reports suggest the alveolar and bronchial epithelium as likely sources,17 23 25 and expression appears to be regulated by proteinase-activated receptors 17 18. In addition, while the authors have demonstrated that CCL2/7 are directly chemotactic for neutrophils, there may be additional mechanisms through which CCL2/7 induce neutrophil recruitment, such as via activation of resident alveolar macrophages or epithelial cells to secrete CXC chemokines or by inducing monocyte recruitment, which in turn may facilitate neutrophil recruitment 26.…”

Coagulopathies and inflammatory diseases: ‘…glimpse of a Snark’

“…In a model of glomerulonephritis, thrombin induced PAR-1-dependent inflammation [12]. In an infectious model with Streptococcus pneumoniae , antagonizing PAR-1 reduced neutrophil recruitment [13]. During lethal sepsis, dendritic cells (DCs) expressing PAR-1 amplified both inflammatory and thrombotic responses through the sphingosine-1-phosphate 3 (S1P3) signaling pathway [14].…”