Wells, U. M., S. Duneclift, and J. G. Widdicombe. H₂O₂ increases sheep tracheal blood flow, permeability, and vascular response to luminal capsaicin. J. Appl. Physiol. 82(2): 621-631, 1997.Exogenous hydrogen peroxide (H₂O₂) causes airway epithelial damage in vitro. We have studied the effects of luminal H₂O₂ in the sheep trachea in vivo on tracheal permeability to low-molecular-weight hydrophilic (technetium-99m-labeled diethylenetriamine pentaacetic acid; ^99mTc-DTPA) and lipophilic ([¹⁴C]antipyrine; [¹⁴C]AP) tracers and on the tracheal vascular response to luminal capsaicin, which stimulates afferent nerve endings. A tracheal artery was perfused, and tracheal venous blood was collected. H₂O₂ exposure (10 mM) reduced tracheal potential difference (42.0 ± 6.4 mV) to zero. It increased arterial and venous flows (56.7 ± 6.1 and 57.3 ± 10.0%, respectively; n = 5, P < 0.01, paired t-test) but not tracheal lymph flow (unstimulated flow 5.0 ± 1.2 µl ^· min^{1 ·} cm¹, n = 4). During H₂O₂ exposure, permeability to ^99mTc-DTPA increased from 2.6 to 89.7 × 10⁷ cm/s (n = 5, P < 0.05), whereas permeability to [¹⁴C]AP (3,312.6 × 10⁷ cm/s, n = 4) was not altered significantly (2,565 × 10⁷ cm/s). Luminal capsaicin (10 µM) increased tracheal blood flow (10.1 ± 4.1%, n = 5) and decreased venous ^99mTc-DTPA concentration (19.7 ± 4.0, P < 0.01), and these effects were significantly greater after epithelial damage (28.1 ± 6.0 and 45.7 ± 4.3%, respectively, P < 0.05, unpaired t-test). Thus H₂O₂ increases the penetration of a hydrophilic tracer into tracheal blood and lymph but has less effect on a lipophilic tracer. It also enhances the effects of luminal capsaicin on blood flow and tracer uptake.