Post by Max on Jun 13, 2005 18:19:17 GMT -5
Several case reports of lung related effects
Several case reports describe an aggravation of asthma, induced bronchoconstriction or induced bronchoconstriction during physical exercise in human acne-subjects exposed to (Ro)accutane [1, 2, 3 and more]. Hoffman la Roche itself has reported the associtation "bronchospasms, with or without history of asthma, respiratory infection and voice alteration" in human subjects exposed to (Ro)accutane [0]. The long term effects on lung function are not known. Suggested effects on the lungs include inhibition of cell proliferation, apoptosis, alteration of epithelial cell function and inhibition of angiogenesis, the formation of blood vessels, as seen in cancer therapy.
Causal links
HB-EGF
The epidermal growth factor receptor (EGFR), an important signaling pathway in airway biology, is stimulated by compressive stress applied to human airway epithelial cells. Although the EGFR ligand, heparin-binding epidermal growth factor-like growth factor (HB-EGF), is known to be released as a result of this stimulation, whether compressive stress enhances expression of other EGFR ligands, and the duration of mechanical compression required to initiate this response, is not known [4]. Heparin affin regulatory peptide (HARP), also known as pleiotrophin or heparin-binding growth-associated molecule, is an 18-kDa growth factor that has a high affinity for heparin. It constitutes with midkine and retinoic acid heparin-binding protein, a family of structurally related heparin-binding growth factors. A growing body of evidence indicates that HARP is involved in the control of cellular proliferation, migration and differentiation and plays a significant role in tumor growth and angiogenesis [7].
Inhibition of angiogenesis, the formation of blood vessels, is a current cancer strategy. However, the effects on the healthy lung capacity is not fully evaluated. No measurments of capacity of oxygen uptake in (Ro)accutane exposed patients has been performed.
Histamine
Marked basophilia and severe symptoms due to hyperhistaminemia have been reported after the exposure in APL subjects with all-trans retinoic acid [5].
TGF-beta1
While the addition of TGF-beta1 or retinoic acid to monkey normal lung bronchial 12MBr6 cells and human lung cancer NCI-H727 cells increased DENTT protein production, TGF-beta1 together with retinoic acid resulted in a more sustained increase in DENTT production than with TGF-beta1 or retinoic acid alone. Transient transfection studies showed that ectopic DENTT expression significantly increased TGF-beta1-responsive 3TP-Lux and CAGA12-Lux reporter transcription in 12MBr6 and NCI-H727 cells with TGF-beta1 addition, while ectopic DENTT expression had no significant effect on the transcription of a retinoic acid-responsive element reporter in the presence of retinoic acid or TGF-beta1 [6].
IgE dependent respiratory infections
IgE dependent allergic diseases are initiated by multivalent binding of allergens to IgE that is bound to receptors with high affinity for IgE on mast cells. Mast cells also express functional Toll Like Receptors (TLRs) which may account for the protection conferred by mast cells against bacterial infections in animal models. Activated mast cells release an array of potent inflammatory mediators by rapid discharge of preformed mediators in granules, the generation of inflammatory lipids from arachidonic acid, and the production of numerous Th2-type cytokines and chemokines. Stimulation of mast cells via TLR2 and TLR4 results primarily in generation of cytokines such as IL-4, IL-5, IL-6, IL-10, IL-13 and TNFalpha [8].
Several case reports describe an aggravation of asthma, induced bronchoconstriction or induced bronchoconstriction during physical exercise in human acne-subjects exposed to (Ro)accutane [1, 2, 3 and more]. Hoffman la Roche itself has reported the associtation "bronchospasms, with or without history of asthma, respiratory infection and voice alteration" in human subjects exposed to (Ro)accutane [0]. The long term effects on lung function are not known. Suggested effects on the lungs include inhibition of cell proliferation, apoptosis, alteration of epithelial cell function and inhibition of angiogenesis, the formation of blood vessels, as seen in cancer therapy.
Causal links
HB-EGF
The epidermal growth factor receptor (EGFR), an important signaling pathway in airway biology, is stimulated by compressive stress applied to human airway epithelial cells. Although the EGFR ligand, heparin-binding epidermal growth factor-like growth factor (HB-EGF), is known to be released as a result of this stimulation, whether compressive stress enhances expression of other EGFR ligands, and the duration of mechanical compression required to initiate this response, is not known [4]. Heparin affin regulatory peptide (HARP), also known as pleiotrophin or heparin-binding growth-associated molecule, is an 18-kDa growth factor that has a high affinity for heparin. It constitutes with midkine and retinoic acid heparin-binding protein, a family of structurally related heparin-binding growth factors. A growing body of evidence indicates that HARP is involved in the control of cellular proliferation, migration and differentiation and plays a significant role in tumor growth and angiogenesis [7].
Inhibition of angiogenesis, the formation of blood vessels, is a current cancer strategy. However, the effects on the healthy lung capacity is not fully evaluated. No measurments of capacity of oxygen uptake in (Ro)accutane exposed patients has been performed.
Histamine
Marked basophilia and severe symptoms due to hyperhistaminemia have been reported after the exposure in APL subjects with all-trans retinoic acid [5].
TGF-beta1
While the addition of TGF-beta1 or retinoic acid to monkey normal lung bronchial 12MBr6 cells and human lung cancer NCI-H727 cells increased DENTT protein production, TGF-beta1 together with retinoic acid resulted in a more sustained increase in DENTT production than with TGF-beta1 or retinoic acid alone. Transient transfection studies showed that ectopic DENTT expression significantly increased TGF-beta1-responsive 3TP-Lux and CAGA12-Lux reporter transcription in 12MBr6 and NCI-H727 cells with TGF-beta1 addition, while ectopic DENTT expression had no significant effect on the transcription of a retinoic acid-responsive element reporter in the presence of retinoic acid or TGF-beta1 [6].
IgE dependent respiratory infections
IgE dependent allergic diseases are initiated by multivalent binding of allergens to IgE that is bound to receptors with high affinity for IgE on mast cells. Mast cells also express functional Toll Like Receptors (TLRs) which may account for the protection conferred by mast cells against bacterial infections in animal models. Activated mast cells release an array of potent inflammatory mediators by rapid discharge of preformed mediators in granules, the generation of inflammatory lipids from arachidonic acid, and the production of numerous Th2-type cytokines and chemokines. Stimulation of mast cells via TLR2 and TLR4 results primarily in generation of cytokines such as IL-4, IL-5, IL-6, IL-10, IL-13 and TNFalpha [8].