A decrease in the activity of proprotein convertase subtilisin/kexin type 9 (PCSK9) increases the amount of lowdensity lipoprotein (LDL) receptors on liver cells and, therefore, LDL clearance. The clearance of lipids from pathogens is related to endogenous lipid clearance; thus, PCSK9 may also regulate removal of pathogen lipids such as lipopolysaccharide (LPS). Compared to controls, Pcsk9 knockout mice displayed decreases in inflammatory cytokine production and in other physiological responses to LPS. In human liver cells, PCSK9 inhibited LPS uptake, a necessary step in systemic clearance and detoxification. Pharmacological inhibition of PCSK9 improved survival and inflammation in murine polymicrobial peritonitis. Human PCSK9 loss-of-function genetic variants were associated with improved survival in septic shock patients and a decrease in inflammatory cytokine response both in septic shock patients and in healthy volunteers after LPS administration. The PCSK9 effect was abrogated in LDL receptor (LDLR) knockout mice and in humans who are homozygous for an LDLR variant that is resistant to PCSK9. Together, our results show that reduced PCSK9 function is associated with increased pathogen lipid clearance via the LDLR, a decreased inflammatory response, and improved septic shock outcome.

We conclude that an MPO inhibitor is able to stop progression of emphysema and small airway remodeling and to partially protect against pulmonary hypertension, even when treatment starts relatively late in the course of long-term smoke exposure, suggesting that inhibition of MPO may be a novel and useful therapeutic treatment for COPD. Protection appears to relate to inhibition of oxidative damage and down-regulation of the smoke-induced inflammatory response.

The AA genotype of ADRB2 rs1042717, identifying homozygotes for the CysGlyGln haplotype, was associated with increased mortality and more organ dysfunction in septic shock.

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Conditions such as asthma and inflammatory bowel disease are characterized by aberrant smooth muscle contraction. It has proven difficult to develop human cellbased models that mimic acute muscle contraction in 2D in vitro cultures due to the nonphysiological chemical and mechanical properties of lab plastics that do not allow for muscle cell contraction. To enhance the relevance of in vitro models for human disease, we describe how functional 3D smooth muscle tissue that exhibits physiological and pharmacologically relevant acute contraction and relaxation responses can be reproducibly fabricated using a unique microfluidic 3D bioprinting technology. Primary human airway and intestinal smooth muscle cells were printed into rings of muscle tissue at high density and viability. Printed tissues contracted to physiological concentrations of histamine (0.01-100 μM) and relaxed to salbutamol, a pharmacological compound used to relieve asthmatic exacerbations. The addition of TGFβ to airway muscle rings induced an increase in unstimulated muscle shortening and a decreased response to salbutamol, a phenomenon which also occurs in chronic lung diseases. Results indicate that the 3D bioprinted smooth muscle is a physiologically relevant in vitro model that can be utilized to study disease pathways and the effects of novel therapeutics on acute contraction and chronic tissue stenosis.

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BACKGROUND: Four-and-a-half LIM domain protein-2 (FHL2) is expressed in endothelial and vascular smooth muscle cells. It negatively regulates endothelial cell survival and migration, but its role in atherogenesis is unknown. METHODS AND RESULTS: To investigate the role of FHL2 in atherosclerosis, FHL2-deficient (FHL2-/-) mice were crossed with ApoE-deficient (ApoE-/-) mice, to generate ApoE/FHL2-/-mice. After 7 weeks of high fat diet, ApoE/FHL2-/-mice had significantly smaller (P<0.05) atherosclerotic plaques than ApoE-/-mice in the aortic sinus (0.14AE0.02 vs. 0.29AE0.04 mm2), the brachiocephalic artery (0.03AE0.008 vs. 0.07AE0.01 mm2) and the aorta (6.9AE0.9 vs 10.3AE1%), assessed by oil red O staining. This was associated with enhanced collagen (16AE2 vs 8.6AE3 %) and smooth muscle cell (4.5AE0.8 vs 1.8AE0.5%) contents within the plaques of ApoE/FHL-2-/-mice. Moreover, macrophage content within plaques was reduced 2-fold in ApoE/FHL2-/-vs ApoE-/-mice (P<0.05). This could be explained, in part, by the 40% reduction in aortic ICAM-1 mRNA and 55% reduction in VCAM-1 protein expression in the plaque. Furthermore, aortic gene expression of Cx3cl1 and Ccl5 was increased in ApoE/FHL2-/-vs ApoE-/-mice, suggesting that different monocyte populations might be recruited to the plaques. Peritoneal thioglycollate injection elicited equivalent numbers of monocytes and macrophages in both groups, but a significantly lower number of pro-inflammatory Ly6C high monocytes were recruited in ApoE/FHL2-/-vs ApoE-/-mice (8AE3 vs 18AE4%). Furthermore, mRNA levels of Cx3cr1 were 2-fold higher in monocytes from ApoE/FHL2-/-mice compared with ApoE-/mice. Finally, we also investigated the potential importance of myeloid cell FHL2 deficiency in atherosclerosis. ApoE-/-or ApoE/ FHL2-/-mice were lethally irradiated and transplanted with ApoE-/or ApoE/FHL2-/-bone marrow. After recovery and 7 weeks of high fat diet, both chimeric groups developed smaller plaques than ApoE-/-mice transplanted with ApoE-/-bone marrow. CONCLUSION: These results suggest that FHL2 in both myeloid and vascular cells may play an important role in atherosclerosis by promoting pro-inflammatory chemokine production, adhesion molecule expression, and pro-inflammatory monocyte recruitment.