Antifibrotic and Anti-inflammatory Activity of the Tyrosine Kinase Inhibitor Nintedanib in Experimental Models of Lung Fibrosis

Abstract

The tyrosine kinase inhibitor nintedanib (BIBF 1120) is in clinical development for the treatment of idiopathic pulmonary fibrosis. To explore its mode of action, nintedanib was tested in human lung fibroblasts and mouse models of lung fibrosis. Human lung fibroblasts expressing platelet-derived growth factor (PDGF) receptor-a and -b were stimulated with platelet-derived growth factor BB (homodimer) (PDGF-BB). Receptor activation was assessed by autophosphorylation and cell proliferation by bromodeoxyuridine incorporation. Transforming growth factor b (TGFb)-induced fibroblast to myofibroblast transformation was determined by a-smooth muscle actin (aSMA) mRNA analysis. Lung fibrosis was induced in mice by intratracheal bleomycin or silica particle administration. Nintedanib was administered every day by gavage at 30, 60, or 100 mg/kg. Preventive nintedanib treatment regimen started on the day that bleomycin was administered. Therapeutic treatment regimen started at various times after the induction of lung fibrosis. Bleomycin caused increased macrophages and lymphocytes in the bronchoalveolar lavage (BAL) and elevated interleukin-1b (IL-1b), tissue inhibitor of metalloproteinase-1 (TIMP-1), and collagen in lung tissue. Histology revealed chronic inflammation and fibrosis. Silica-induced lung pathology additionally showed elevated BAL neutrophils, keratinocyte chemoattractant (KC) levels, and granuloma formation. Nintedanib inhibited PDGF receptor activation, fibroblast proliferation, and fibroblast to myofibroblast transformation. Nintedanib significantly reduced BAL lymphocytes and neutrophils but not macrophages. Furthermore, interleukin-1b, KC, TIMP-1, and lung collagen were significantly reduced. Histologic analysis showed significantly diminished lung inflammation, granuloma formation, and fibrosis. The therapeutic effect was dependent on treatment start and duration. Nintedanib inhibited receptor tyrosine kinase activation and the proliferation and transformation of human lung fibroblasts and showed antifibrotic and anti-inflammatory activity in two animal models of pulmonary fibrosis. These results suggest that nintedanib may impact the progressive course of fibrotic lung diseases such as idiopathic pulmonary fibrosis.

Role of α1 and α2 chains of type IV collagen in early fibrotic lesions of idiopathic interstitial pneumonias and migration of lung fibroblasts

“…35 In general, an animal model of bleomycin-induced lung fibrosis is a fibrosis model with intraluminal buds of OP as a general process of repair from acute or subacute lung injury, 36 but not a fibrosis model with fibroblastic foci of UIP as chronic, progressive and irreversible pulmonary damage with honeycomb change. 37,38 In fact, to date, numerous agents have been shown to inhibit the fibrotic Type IV collagen in interstitial pneumonia H Urushiyama et al changes in this animal model, 39 but a few of these agents, such as pirfenidone 40,41 and nintedanib, 42,43 have shown a comparable antifibrotic effect on cases of IPF/UIP in humans. The radiographic images of COP often demonstrate migratory consolidation corresponding to fibrotic lesions of OP, and thus the progression in fibrosis of COP is more acute (median, o3 months) 1,2 than that of IPF which demonstrates a slow and gradual progression over many years.…”

Idiopathic pulmonary fibrosis: The current state of the problem

“…Доказан управляемый профиль безопасности. На основании опыта иссле-дования TOMORROW рекомендованы следующие меры в иссле-довании INPULSIS [36].…”

“…Следующее исследование INPULSIS [36] проведено в 205 центрах 24 стран. в результате проведенных исследований получены основ-ные данные по эффективности нинтеданиба.…”

Влияние 5-Амино-4-(1,3-Бензотиазол-2-Ин)-1-(3-Метоксифенил)-1,2-Дигидро-3h-Пиррол-3-Она На Состояние Органов Пищеварения При Экспериментальном Раке Толстого Кишечника Крыс

“…Òàêèì îáðàçîì, áëîêèðóÿ ðåöåïòîðû ê óêàçàííûì ôàêòîðàì, Ä1 èíãèáèðóåò ïðîâîñïàëèòåëüíûé ñèãíàë. Ïðîòèâî-âîñïàëèòåëüíîå äåéñòâèå èíãèáèòîðîâ ðåöåïòîðîâ ðîñ-òîâûõ ôàêòîðîâ òàêaeå áûëî ïîêàçàíî [18]. Âîçìîaeíî, â ïðîòèâîâîñïàëèòåëüíîì è ïðîòèâîîïóõîëåâîì âîçäåé-ñòâèè Ä1 ïðèíèìàþò ó÷àñòèå åãî àíòèîêñèäàíòíûå ñâîéñòâà, îáóñëîâëåííûå íàëè÷èåì â ñòðóêòóðå ìîëåêó-ëû äâîéíûõ ñâÿçåé ìåaeäó àòîìàìè óãëåðîäà è àìèíî-ãðóïïû [4].…”