The pathogenesis of pulmonary fibrosis involves lung epithelial injury and aberrant proliferation of fibroblasts, and results in progressive pulmonary scarring and declining lung function. In vitro, fibroblast growth factor (FGF) 2 promotes myofibroblast differentiation and proliferation in cooperation with the profibrotic growth factor, transforming growth factor-b1, but the in vivo requirement for FGF2 in the development of pulmonary fibrosis is not known. The bleomycin model of lung injury and pulmonary fibrosis was applied to Fgf2 knockout (Fgf2 2/2) and littermate control mice. Weight loss, mortality, pulmonary fibrosis, and histology were analyzed after a single intranasal dose of bleomycin. Inflammation was evaluated in bronchoalveolar lavage (BAL) fluid, and epithelial barrier integrity was assessed by measuring BAL protein and Evans Blue dye permeability. Fgf2 is expressed in mouse and human lung epithelial and inflammatory cells, and, in response to bleomycin, Fgf2 2/2 mice have significantly increased mortality and weight loss. Analysis of BAL fluid and histology show that pulmonary fibrosis is unaltered, but Fgf2 2/2 mice fail to efficiently resolve inflammation, have increased BAL cellularity, and, importantly, deficient recovery of epithelial integrity. Fgf2 2/2 mice similarly have deficient recovery of club cell secretory protein 1 bronchial epithelium in response to naphthalene. We conclude that FGF2 is not required for bleomycin-induced pulmonary fibrosis, but rather is essential for epithelial repair and maintaining epithelial integrity after bleomycin-induced lung injury in mice. These data identify that FGF2 acts as a protective growth factor after lung epithelial injury, and call into question the role of FGF2 as a profibrotic growth factor in vivo.Keywords: fibroblast growth factor 2; bleomycin; pulmonary fibrosis; lung injury; alveolar epithelial repair Clinical RelevanceFibroblast growth factors (FGFs) and, in particular, FGF2, are implicated in the pathogenesis of pulmonary fibrosis and recovery from airway epithelial cell (AEC) injury; however, the in vivo requirement for FGF2 in the development of pulmonary fibrosis is not known. In this study, we have found that mice lacking FGF2 do not show altered levels of fibrosis in response to bleomycin, indicating that FGF2 is dispensable for the generation of bleomycin-induced pulmonary fibrosis. In addition, we show that FGF2 knockout mice have increased mortality and weight loss in response to bleomycin, accompanied by deficient recovery of mature alveolar epithelium and epithelial barrier function. These findings suggest that FGF2 is required for lung epithelial recovery, that pharmacological inhibition of FGF signaling could impair the response to lung injury, and that FGF2 administration or augmentation may have therapeutic benefit for lung injury.Lung alveolar epithelial cell (AEC) injury can be caused by a variety of insults, including infection, trauma, aspiration, and sepsis. Chronic AEC injury of unknown origin is central to ...

Abdominal aortic aneurysms (AAAs) involve slow proteolysis and loss of structural matrix components (collagen and elastin), which lead to wall thinning, weakening and ultimate rupture. At this time, no established non-surgical therapy is available to slow or arrest AAA growth. Inhibiting matrix metalloproteases (MMPs; e.g. MMP2 and -9) overexpressed within AAAs is insufficient to arrest AAA growth, since resident smooth muscle cells (SMCs) are poorly elastogenic and cannot overcome elastolysis to reinstate a healthy elastic matrix. Towards overcoming this limitation, this first study sought to determine the utility of rat bone marrow mesenchymal stem cell (BM-MSC)-derived SMCs to stimulate elastin and elastic matrix synthesis and assembly by aneurysmal SMCs (EaRASMCs). BM-MSCs were successfully differentiated into cells of an SMC lineage (SMLCs). Our study indicates that BM-MSC-derived SMLCs secrete trophic factors, contained in conditioned medium (CM) from their cultures, that, when exposed to EaRASMC cultures in real time, stimulate elastin precursor and matrix deposition and crosslinking by these elastogenically deficient cells, with added benefits in terms of attenuating MMPs, specifically MMP9. The results thus lend support to a proposed cell therapy for AAAs, based on the use of BM-MSC-derived SMLCs. Although we observed no particular improvement in elastic fibre formation, no attenuation of MMP2 activity and increase in amounts of active MMP2 enzyme, we believe that this study justifies follow-up studies to improve upon these outcomes. Future studies will explore the effects of concentrated CM collected from long-term SMLC cultures on EaRASMCs and also investigate the elastogenic output of SMLCs themselves. Copyright © 2014 John Wiley & Sons, Ltd.

Background: Mutations in fibulin-4 cause autosomal recessive cutis laxa 1B, characterized by loose skin with vascular, lung, and skeletal abnormalities. Results: A mouse strain carrying a recurrent fibulin-4 missense mutation was generated and characterized. Conclusion: Mutant mice recapitulate the complete clinical features of the disease. Significance: The study provides the first evidence that fibulin-4 regulates collagen fibrillogenesis.

Analyses of fatty acids with carbon numbers between C12 and C22 are reported for five Great Barrier Reef sponges. These analyses indicate that phototrophic cyanobacterial symbionts (blue-green algae) present in three of the sponges are chemically distinct, whereas the other two sponges do not contain cyanobacterial symbionts. All the sponges contain other, nonphototrophic bacteria. The fatty acid analyses indicate that the non-phototrophic bacterial populations present in the different sponges are distinct in both their chemical compositions and their abundances. Nonphototrophic bacteria are estimated to account for between 60 and 350 micrograms/g (extractable fatty acids:tissue wet weight), whereas cyanobacteria account for between 10 and 910 micrograms/g. One sponge (Pseudaxinyssa sp.) contains a relatively large amount of the isoprenoid acid, 4, 8, 12-trimethyltridecanoic acid; this acid is presumed to be derived from phytol, a degradation product of chlorophyll. This sponge also contains relatively large amounts of the nonmethylene interrupted fatty acid, octadeca-5,9-dienoic acid. Analyses of interior and cyanobacteria-rich surface tissues of this sponge indicate that these two acids are probably not associated with the symbiotic cyanobacteria.

Decreased elastin in mice (Eln+/−) yields a functioning vascular system with elevated blood pressure and increased arterial stiffness that is morphologically distinct from wild-type mice (WT). Yet, function is retained enough that there is no appreciable effect on life span and some mechanical properties are maintained constant. It is not understood how the mouse modifies the normal developmental process to produce a functioning vascular system despite a deficiency in elastin. To quantify changes in mechanical properties, we have applied a fiber-based constitutive model to mechanical data from the ascending aorta during postnatal development of WT and Eln+/− mice. Results indicate that the fiber-based constitutive model is capable of distinguishing elastin amounts and identifying trends during development. We observe an increase in predicted circumferential stress contribution from elastin with age, which correlates with increased elastin amounts from protein quantification data. The model also predicts changes in the unloaded collagen fiber orientation with age, which must be verified in future work. In Eln+/− mice, elastin amounts are decreased at each age, along with the predicted circumferential stress contribution of elastin. Collagen amounts in Eln+/− aorta are comparable to WT, but the predicted circumferential stress contribution of collagen is increased. This may be due to altered organization or structure of the collagen fibers. Relating quantifiable changes in arterial mechanics with changes in extracellular matrix (ECM) protein amounts will help in understanding developmental remodeling and in producing treatments for human diseases affecting ECM proteins.