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Excerpt: Morgan et al. (1) concluded that cystic fibrosis (CF) in children and adolescents with a high baseline forced expiratory volume (FEV1) were less likely to have a therapeutic intervention or slower rate of FEV1 decline after a single acute decline in FEV1 of 10%. This conclusion is not well supported due to the arbitrary criteria used for defining a pulmonary exacerbation, as explained below.

Pseudomonas aeruginosa is a Gram-negative bacterium implicated in several clinical contexts. In its association with immunocompromised hosts including cystic fibrosis patients, P. aeruginosa is able to exploit the host immune response to acquire key factors essential to its adaptation. As such, key virulence factors including the Type III Secretion System (T3SS), initially essential in acute infection, is reduced in its significance in chronic colonization. On the contrary, other phenotypes are essential for the altered priorities in chronic colonization. The signals of the host immune response initiating the phenotypic switch from the expression of acute virulence factors to chronic virulence factors have not been well defined. Additionally, the function of the type VI secretion system (T6SS), a protein secretion apparatus, in chronic infection has been well established. Clinical isolates obtained from acute and chronic P. aeruginosa infections suggested selective regulation of the T6SS, namely up regulation of the H3-T6SS in chronic infection. We used murine models of infection to understand the in vivo transcriptional regulation of the T6SS of PAO1. Itaconate, an anti-inflammatory metabolite generated by the host, selectively upregulated transcription of a H3-T6SS-associated locus, vgrG3. Here we present evidence to show how the host immune response, namely metabolic changes in response to infection may be exploited to support the organism’s adaptation to the lung microenvironment. In the evaluation of such a phenotypic response notable in chronic infections, the Type VI Secretion System (T6SS) of P. aeruginosa is selectively regulated by a host-specific metabolic product, itaconate. While P. aeruginosa contains genetic clusters for three (H1-, H2-, and H3-T6SS) evolutionarily distinct T6SSs, we found the H3-T6SS to be up-regulated significantly (p<0.05) in the presence of this anti-inflammatory signal. Characterization of this response reveals that itaconate induces metabolic stress in P. aeruginosa. In an acute pneumoniae mouse model, deletion of the H3-T6SS locus results in increased colonization of the murine lung. Analysis of bronchoalveolar lavage fluid from wild type and H3-T6SS null-infected mice reveals alterations in metabolic pathways including purine metabolism, carbon metabolism, and arginine biosynthesis. Overall our work outlines the H3-T6SS as a phenotypic response to metabolic stress induced by the host immune response, serving to mediate pathways essential in pathogenesis. Further understanding of such phenotypes as the T6SS implicated in chronic infection is essential in treatment interventions in the clinic.

Calcific aortic valve disease (CAVD) is a highly prevalent and progressive disorder that ultimately causes gradual narrowing of the left ventricular outflow orifice with ensuing devastating hemodynamic effects on the heart. Calcific mineral accumulation is the hallmark pathology defining this process; however, fibrotic extracellular matrix (ECM) remodeling that leads to extensive deposition of fibrous connective tissue and distortion of the valvular microarchitecture similarly has major biomechanical and functional consequences for heart valve function. Significant advances have been made to unravel the complex mechanisms that govern these active, cell-mediated processes, yet the interplay between fibrosis and calcification and the individual contribution to progressive extracellular matrix stiffening require further clarification. Specifically, we discuss (1) the valvular biomechanics and layered ECM composition, (2) patterns in the cellular contribution, temporal onset, and risk factors for valvular fibrosis, (3) imaging valvular fibrosis, (4) biomechanical implications of valvular fibrosis, and (5) molecular mechanisms promoting fibrotic tissue remodeling and the possibility of reverse remodeling. This review explores our current understanding of the cellular and molecular drivers of fibrogenesis and the pathophysiological role of fibrosis in CAVD.

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