All 3 SKIs, BIRB796, dasatinib, and R343, as well as the combinations BIRB796/dasatinib and dasatinib/R343 did not significantly inhibit LPS-induced CXCL8 in non-COPD HASMCs. In contrast, the BIRB796/R343 double combination and the BIRB796/dasatinib/R343 triple combination both showed strong inhibitory effects (see Fig E4, A and B, in this article's Online Repository at www.jacionline.org). This suggests dominant roles for p38MAPK and Syk but not for Src in the regulation of LPS-induced CXCL8. As the BIRB796/dasatinib combined treatment, the NSKI RV568 did not significantly inhibit LPS-induced CXCL8. In contrast, RV1088 potently suppressed CXCL8 in LPS-exposed HASMCs and was almost equally effective as the BIRB796/R343 double and the BIRB796/dasatinib/R343 triple combination. RV1088 was superior to any SKI in single treatments (Fig E4, A and B). In COPD HASMCs, RV1088 almost completely inhibited LPS-induced CXCL8. RV1088 was superior to RV568, to BIRB796, and to FP, all of which only showed weak inhibitory effects (Fig 1, E and F; Table I). Dasatinib and R343 in single treatments and the dasatinib/ R343 combination did not inhibit LPS-induced GM-CSF in non-COPD HASMCs. BIRB796 single treatment as well as the BIRB796/R343 and BIRB796/dasatinib combinations all partially suppressed LPS-induced GM-CSF, and BIRB796/ dasatinib was most effective. The BIRB796/dasatinib/R343 triple combination was superior to any double combination (see Fig E5, A and B, in this article's Online Repository at www.jacionline. org). This suggests that p38MAPK-, Src-, and Syk-family kinases are involved in the regulation of LPS-induced GM-CSF. RV568 and RV1088 were equally effective as the BIRB796/dasatinib double or BIRB796/dasatinib/R343 triple combination, respectively. RV1088 was superior to RV568 and to any single and double treatment (Fig E5, A and B). In COPD HASMCs, RV1088 completely inhibited LPS-induced GM-CSF. RV1088 was superior to RV568 and to BIRB796, both of which showed partial inhibitory effects (Fig 1, G and H; Table I). RV1088 was by trend also superior to the strong effects of FP. Data in the Online Repository (see Figs E6 and E7 in this article's Online Repository at www.jacionline.org) suggest (1) that differential sensitivities of CXCL8 and GM-CSF for NSKIs in different models depend on transcriptional regulation and (2) that NSKIs affect posttranscriptional CXCL8 regulation in the TNF-a but not in the LPS model. Our data provide strong evidence for a utility of a new anti-inflammatory therapeutic strategy in COPD: NSKIs suppress corticosteroid-sensitive and corticosteroid-insensitive cytokine production in in vitro models of COPD and they are superior to sole p38MAPK inhibition and to SKIs that target Src and Syk. Targeting p38MAPK, Src, and Syk may be more effective than targeting only 2 of these 3 kinases (details are discussed in this article's Online Repository at www.jacionline.org). The limitation of this study is a lack of kinase-specific approaches using siRNA or knockout experiments. We cannot exclude off-ta...