TGF-β1 signaling is a critical driver of collagen accumulation and fibrotic disease but also a vital suppressor of inflammation and epithelial cell proliferation. The nature of this multifunctional cytokine has limited the development of global TGF-β1 signaling inhibitors as therapeutic agents. We conducted phenotypic screens for small molecules that inhibit TGF-β1–induced epithelial-mesenchymal transition without immediate TGF-β1 receptor (TβR) kinase inhibition. We identified trihydroxyphenolic compounds as potent blockers of TGF-β1 responses (IC₅₀ ~50 nM), Snail1 expression, and collagen deposition in vivo in models of pulmonary fibrosis and collagen-dependent lung cancer metastasis. Remarkably, the functional effects of trihydroxyphenolics required the presence of active lysyl oxidase–like 2 (LOXL2), thereby limiting effects to fibroblasts or cancer cells, the major LOXL2 producers. Mechanistic studies revealed that trihydroxyphenolics induce auto-oxidation of a LOXL2/3–specific lysine (K731) in a time-dependent reaction that irreversibly inhibits LOXL2 and converts the trihydrophenolic to a previously undescribed metabolite that directly inhibits TβRI kinase. Combined inhibition of LOXL2 and TβRI activities by trihydrophenolics resulted in potent blockade of pathological collagen accumulation in vivo without the toxicities associated with global inhibitors. These findings elucidate a therapeutic approach to attenuate fibrosis and the disease-promoting effects of tissue stiffness by specifically targeting TβRI kinase in LOXL2-expressing cells.

Mycoplasma pneumoniae infection has been linked to poor asthma outcomes. M. pneumoniae produces an ADP-ribosylating and vacuolating toxin called community-acquired respiratory distress syndrome (CARDS) toxin that has a major role in inflammation and airway dysfunction. The objective was to evaluate the immunopathological effects in primates exposed to M. pneumoniae or CARDS toxin. A total of 13 baboons were exposed to M. pneumoniae or CARDS toxin. At Days 7 and 14, BAL fluid was collected and analyzed for cell count, percent of each type of cell, CARDS toxin by PCR, CARDS toxin by antigen capture, eosinophilic cationic protein, and cytokine profiles. Serum IgM, IgG, and IgE responses to CARDS toxin were measured. All animals had a necropsy for analysis of the histopathological changes on lungs. No animal developed signs of infection. The serological responses to CARDS toxin were variable. At Day 14, four of seven animals exposed to M. pneumoniae and all four animals exposed to CARDS toxin developed histological “asthma-like” changes. T cell intracellular cytokine analysis revealed an increasing ratio of IL-4/IFN-γ over time. Both M. pneumoniae and CARDS toxin exposure resulted in similar histopathological pulmonary changes, suggesting that CARDS toxin plays a major role in the inflammatory response.

To determine the frequency and prognosis of the various causes oflow systemic vascular resistance (SVR). Analysis of consecutive patients over a 5-year period;retrospective review. Medical intensive care unit of a large university hospital. Fifty-five patients with unexplained hypotension and a SVR lessthan 800 dynes × s/cm⁵. There are minimal data in the medical literature determining thefrequency or outcome of patients with a low SVR that is unrelated to sepsis orthe sepsis syndrome. We retrospectively reviewed and analyzed all hemodynamicdata in a large university hospital over a 5-year period to determine thefrequency and prognosis of the various causes of low SVR. Fifty-five patientswith unexplained hypotension and a SVR less than800dynes×s/cm⁵were identified. Twenty-two patients (Groups 1 and 2) met the criteria for sepsissyndrome. The mean SVR for this group was 445 ±168 dynes×s/cm⁵ with an associated mortality of 50%. Group 3contained 20 patients with possible sepsis. Thirteen patients (Group 4) werenonseptic. The mean SVR of this group was 435 ±180 dynes × s/cm⁵ with an associated mortality of 46%. Extremelylow SVR (below 450 dynes × s/cm⁵) was associated with asignificantly higher mortality regardless of the etiology. At least a quarter of patients with hypotension and a low SVR havenonseptic etiologies. The patients with nonseptic etiologies have a similarmortality to septic patients. Clinicians should be aware of the wide spectrumof conditions that induce a low SVR.