The microbiome is emerging as a major player in tissue homeostasis in health and disease. Gut microbiome dysbiosis correlates with several autoimmune and metabolic diseases, while high-fat diets and ensuing obesity are known to affect the complexity and diversity of the microbiome, thus modulating pathophysiology. Moreover, the existence of a gut-liver microbial axis has been proposed, which may extend to the lung. In this context, we systematically compared the microbiomes of the gut, liver, and lung of mice fed a high-fat diet to those of littermates fed a matched control diet. We carried out deep sequencing of seven hypervariable regions of the 16S rRNA microbial gene to examine microbial diversity in the tissues of interest. Comparison of the local microbiomes indicated that lung tissue has the least diverse microbiome under healthy conditions, while microbial diversity in the healthy liver clustered closer to the gut. Obesity increased microbial complexity in all three tissues, with lung microbial diversity being the most modified. Obesity promoted the expansion of Firmicutes along the gut-liver-lung axis, highlighting staphylococcus as a possible pathologic link between obesity and systemic pathophysiology, especially in the lungs.

Background: We have previously shown that SHP2 downregulation may predispose fibroblasts to differentiate into myofibroblasts and proposed a role for SHP2 downregulation in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Recent data have shown that SHP2 localizes to the mitochondrial intercristae, and its overexpression enhances mitochondrial metabolism leading to oxidative stress and senescence. Objective: To determine the effect of SHP2 on fibrotic responses. Methods and Results: Primary mouse lung fibroblasts derived from mice carrying a conditional knock-in mutation (D61G/+), rendering the SHP2 catalytic domain constitutively active, had reduced proliferation (1.6-fold, p < 0.05), migration (2-fold, p < 0.05), as well as reduced responsiveness of TGFB-1 induced fibroblasts-to-myofibroblasts differentiation, compared to wild-type ones. Electron microscope analysis revealed that SHP2 ^D61G/+ mouse lung fibroblasts were characterized by mitochondrial abnormalities, including swollen mitochondria with disrupted electron-lucent cristae and an increased number of autophagosomes compared to wild-type ones. SHP2 ^D61G/+ MLFs exhibited increased protein levels of autophagy markers, including LC3B-II and p-62, evidence that was confirmed by immunofluorescence analysis. Mitochondrial function analysis revealed that stable (genotype D61G/+) overexpression of SHP2 led to impaired mitochondrial function, as assessed by decreased mitochondrial membrane potential (1.29-fold, p < 0.05), coupling efficiency (1.82 fold, p < 0.05), oxygen consumption rate (1.9-fold, p < 0.05), and increased reactive oxygen species production both at baseline (1.75-fold, p < 0.05) and following H₂O₂ stimulation (1.63-fold, p < 0.05) compared to wild-type ones (SHP2^+/+). SHP2 ^D61G/+ mouse lung fibroblasts showed enhanced AMPK activity, as well as decreased activation of the mTORC1 signaling pathway, potentially leading to ineffective mitochondrial metabolism and increased autophagy. Conclusions: SHP2 attenuates fibrotic responses in fibroblast cell lines through negative regulation of mitochondrial metabolism and induction of autophagy. SHP2 activation may represent a promising therapeutic strategy for patients with fibrotic lung diseases.

This study focuses on the synthesis and characterization of thermoresponsive hydrogels of poly(lactic acid) (PLA) and poly(ethylene glycol) (PEG), PLA–PEG copolymers, aiming at the targeted and controlled release of deferoxamine (DFO), a clinically applied iron-chelating drug. Triblock (PLA-PEG-PLA) and diblock (mPEG-PLA) copolymers were synthesized using ring-opening polymerization (ROP) with five different PEGs with molecular weights of 1000, 1500, 2000, 4000, and 6000 g/mol and two types of lactide (L-lactide and D-lactide). Emulsions of the polymers in phosphate-buffered saline (PBS) were prepared at concentrations ranging from 10% to 50% w/w to study the sol–gel transition properties of the copolymers. Amongst the synthesized copolymers, only those that demonstrated thermoresponsive sol-to-gel transitions near physiological temperature (37 °C) were selected for further analysis. Structural and molecular confirmation was performed by Nuclear Magnetic Resonance (NMR) and Fourier-transform infrared spectroscopy (FTIR), while the molecular weights were determined via Gel Permeation Chromatography (GPC). The thermal transitions were studied by calorimetry (DSC) and crystallinity via X-ray diffraction (XRD) analysis. DFO-loaded hydrogels were prepared, and their drug release profiles were investigated under simulated physiological conditions (37 °C) for seven days using HPLC analysis. The thermoresponsive characteristics of these systems can offer a promising strategy for injectable drug delivery applications, where micelles serve as drug carriers and undergo in situ gelation, enabling controlled release. This alternative procedure may significantly improve the bioavailability of DFO and enhance patient compliance by addressing key limitations of conventional administration routes.