Amanita phalloides poisoning causes severe liver damage which may be potentially fatal. Several treatments are available, but their effectiveness has not been systematically evaluated. We performed...

Hypothyroidism may reduce, whereas hyperthyroidism may aggravate, asthma symptoms. The mechanisms underlying this relationship are largely unknown. Since thyroid hormones have central roles in cell growth and differentiation, we hypothesized that airway remodeling, in particular increased airway smooth muscle (ASM) mass, may be involved. To address this hypothesis, we investigated the effects of triiodothyronine (T₃) and l-thyroxine (T₄) in the absence and presence of the profibrotic transforming growth factor (TGF)-β1 on human ASM cell phenotype switching. T₃ (1–100 nM) and T₄ (1–100 nM) did not affect basal ASM proliferation. However, when combined with TGF-β1 (2 ng/ml), T₄ synergistically increased the proliferative response, whereas only a minor effect was observed for T₃. In line with a switch from a contractile to a proliferative ASM phenotype, T₄ reduced the TGF-β1-induced contractile protein expression by ∼50%. Cotreatment with T₃ reduced TGF-β1-induced contractile protein expression by ∼25%. The synergistic increase in proliferation was almost fully inhibited by the integrin α_vβ₃ antagonist tetrac (100 nM), whereas no significant effects of the thyroid receptor antagonist 1–850 (3 μM) were observed. Inhibition of MEK1/2, downstream of the integrin α_vβ₃, also inhibited the T₄- and TGF-β1-induced proliferative responses. Collectively, the results indicate that T₄, and to a lesser extent T₃, promotes a proliferative ASM phenotype in the presence of TGF-β1, which is predominantly mediated by the membrane-bound T₄ receptor α_vβ₃. These results indicate that thyroid hormones may enhance ASM remodeling in asthma, which could be of relevance for hyperthyroid patients with this disease.

• Basement membrane composition is changed in the airways of patients with obstructive airway diseases. • Basement membrane changes are linked to disease characteristics in patients. • Mechanisms behind the altered BM composition remain to be elucidated. • Laminin and collagen IV affect key pathological processes in obstructive airway diseases.

Increased extracellular matrix (ECM) deposition and airway smooth muscle (ASM) mass are major contributors to airway remodeling in asthma. Recently, we demonstrated that the ECM protein collagen I, which is increased surrounding asthmatic ASM, induces a proliferative, hypocontractile ASM phenotype. Little is known, however, about the signaling pathways involved. Using bovine tracheal smooth muscle, we investigated the role of focal adhesion kinase (FAK) and downstream signaling pathways in collagen I–induced ASM phenotype modulation. Phosphorylation of FAK was increased during adhesion to both uncoated and collagen I–coated culture dishes, without differences between these matrices. Nor were any differences found in cellular adhesion. Inhibition of FAK activity by overexpression of the FAK deletion mutants FAT (focal adhesion targeting domain) and FRNK (FAK-related nonkinase) attenuated adhesion. After attachment, FAK phosphorylation increased in a time-dependent manner in cells cultured on collagen I, whereas no activation was found on an uncoated plastic matrix. In addition, collagen I increased in a time- and concentration-dependent manner the cell proliferation, which was fully inhibited by FAT and FRNK. Similarly, the specific pharmacologic FAK inhibitor PF-573228 [6-((4-((3-(methanesulfonyl)benzyl)amino)-5-trifluoromethylpyrimidin-2-yl) amino)-3,4-dihydro-1 H -quinolin-2-one] as well as specific inhibitors of p38 mitogen-activated protein kinase (MAPK) and Src also fully inhibited collagen I–induced proliferation, whereas partial inhibition was observed by inhibition of phosphatidylinositol-3-kinase (PI3-kinase) and mitogen-activated protein kinase kinase (MEK). The inhibition of cell proliferation by these inhibitors was associated with attenuation of the collagen I–induced hypocontractility. Collectively, the results indicate that induction of a proliferative, hypocontractile ASM phenotype by collagen I is mediated by FAK and downstream signaling pathways.

Background: Adjunctive host-directed therapies that modulate host immune responses to reduce excessive inflammation and prevent tissue damage in tuberculosis are being investigated. Macrolides, including azithromycin, were shown to possess anti-inflammatory and immune-modulatory effects in addition to their antibacterial effects. In the current trial, we investigated whether azithromycin enhances resolution of systemic and pulmonary inflammation and decreases extracellular matrix-related tissue turnover in tuberculosis patients. Methods: An open-label, randomized, controlled trial was performed. Adult patients with drug-susceptible, pulmonary tuberculosis aged above 18 years were randomly assigned to receive standard antituberculosis care or azithromycin 250 mg orally once daily in addition to standard care (SOC) for 28 days. Results: Twenty-eight patients were included within 4 weeks after initiating antituberculosis treatment. Twelve patients in both arms completed the trial. Participants were mostly young, male, had a history of smoking, and had no comorbidities. No differences in baseline characteristics were observed between the study arms. In blood, azithromycin treatment significantly enhanced the reduction of the tuberculosis marker interferon-γ-induced protein-10 (SOC plus azithromycin, −38% vs SOC alone, −24% vs SOC, P < .05) and the collagen type IV degradation product C4M (−26% vs −11%, P < .05). In sputum, treatment with azithromycin significantly reduced neutrophils (−24% vs 0%, P < .001), neutrophil elastase (−88% vs 75%, P < .01), and transforming growth factor-β (−86% vs −68%, P < .05). No significant effects were observed on other parameters. Treatment with azithromycin appeared to be safe. Conclusions: The addition of azithromycin to standard antituberculosis treatment appears to diminish excess neutrophilic inflammation in patients with pulmonary tuberculosis. Clinical Trials Registration. NCT03160638.