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Anaplastic lymphoma kinase (ALK)‐positive histiocytosis has emerged as a clinically relevant diagnosis featuring a wide span of clinical presentations, which are unified by the presence of ALK‐positive histiocytes on histopathology and molecular drivers involving the ALK kinase gene. This report presents an adult case of multisystem ALK‐positive histiocytosis with xanthogranuloma‐like features on histopathology that was responsive to ALK inhibition, and includes a review of ALK‐positive histiocytoses with cutaneous involvement reported in the literature. A 56‐year‐old male developed a widespread eruption of red‐brown papules on the face, trunk, and upper extremities. Histopathological evaluation revealed a well‐circumscribed, nodular dermal infiltrate of epithelioid histiocytes with Touton giant cells, rare bizarre multinucleated cells, and focal emperipolesis. The lesional cells were positive for CD68 and ALK1 immunohistochemical stains, and negative for CD1a. Next‐generation sequencing identified a DCTN1::ALK fusion. On imaging, he was found to have bone, lung, soft tissue, and salivary gland involvement. ALK inhibition was initiated with alectinib, resulting in rapid improvement of cutaneous lesions and eventual complete resolution of abnormal imaging findings, which was sustained at 24 months of follow‐up. This case adds to the spectrum of ALK‐positive histiocytoses and further demonstrates the positive response with targeted therapy. [ABSTRACT FROM AUTHOR]

Oxidative stress plays an important role in the pathogenesis of pulmonary fibrosis. Heme oxygenase-1 (HO-1) is a key antioxidant enzyme, and overexpression of HO-1 significantly decreases lung inflammation and fibrosis in animal models. Peroxisome proliferator-activated receptor-[gamma] (PPAR[gamma]) is a transcription factor that regulates adipogenesis, insulin sensitization, and inflammation. We report here that the PPAR[gamma] ligands 15d-[PGJ.sub.2] and 2-cyano-3,12-dioxoolean-l,9-dien-28-oic acid (CDDO), which have potent antifibrotic effects in vitro, also strongly induce HO-1 expression in primary human lung fibroblasts. Pharmacological and genetic approaches are used to demonstrate that induction of HO-1 is PPAR[gamma] independent. Upregulation of HO-1 coincides with decreased intracellular glutathione (GSH) levels and can be inhibited by N-acetyl cysteine (NAC), a thiol antioxidant and GSH precursor. Upregulation of HO-1 is not inhibited by Trolox, a non-thiol antioxidant, and does not involve the transcription factors AP-1 or Nrf2. CDDO and 15d-[PGJ.sub.2] contain an [alpha]/[beta] unsaturated ketone that acts as an electrophilic center that can form covalent bonds with free reduced thiols. Rosiglitazone, a PPAR[gamma], ligand that lacks an electrophilic center, does not induce HO-1. These data suggest that in human lung fibroblasts, 15d-[PGJ.sub.2] and CDDO induce HO-1 via a GSH-dependent mechanism involving the formation of covalent bonds between 15d-[PGJ.sub.2] or CDDO and GSH. Inhibiting HO-1 upregulation with NAC has only a small effect on the antifibrotic properties of 15d-[PGJ.sub.2] and CDDO in vitro. These results suggest that CDDO and similar electrophilic PPAR[gamma] ligands may have great clinical potential as antifibrotic agents, not only through direct effects on fibroblast differentiation and function, but indirectly by bolstering antioxidant defenses. 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; myofibroblast; N-acetyl cysteine doi: 10.1152/ajplung.00148.2009.