Autophagy of mucin granules contributes to resolution of airway mucous metaplasia.

Exacerbations of muco-obstructive airway diseases such as COPD and asthma are associated with epithelial changes termed mucous metaplasia (MM). Many molecular pathways triggering MM have been identified; however, the factors that regulate resolution are less well understood. We hypothesized that the autophagy pathway is required for resolution of MM by eliminating excess non-secreted intracellular mucin granules. We found increased intracellular levels of mucins Muc5ac and Muc5b in mice deficient in autophagy regulatory protein, Atg16L1, and that this difference was not due to defects in the known baseline or stimulated mucin secretion pathways. Instead, we found that, in mucous secretory cells, Lc3/Lamp1 vesicles colocalized with mucin granules particularly adjacent to the nucleus, suggesting that some granules were being eliminated in the autophagy pathway rather than secreted. Using a mouse model of MM resolution, we found increased lysosomal proteolytic activity that peaked in the days after mucin production began to decline. In purified lysosomal fractions, Atg16L1-deficient mice had reduced proteolytic degradation of Lc3 and Sqstm1 and persistent accumulation of mucin granules associated with impaired resolution of mucous metaplasia. In normal and COPD derived human airway epithelial cells (AECs), activation of autophagy by mTOR inhibition led to a reduction of intracellular mucin granules in AECs. Our findings indicate that during peak and resolution phases of MM, autophagy activity rather than secretion is required for elimination of some remaining mucin granules. Manipulation of autophagy activation offers a therapeutic target to speed resolution of MM in airway disease exacerbations.

Surgical removal of subfoveal choroidal neovascularization in presumed ocular histoplasmosis: stability of early visual results.

PURPOSE: The authors assess the stability of visual acuity outcomes after the surgical removal of subfoveal choroidal neovascularization in a large series of patients with presumed ocular histoplasmosis syndrome (POHS). METHODS: A retrospective study of 117 consecutive patients undergoing vitrectomy between February 1990 and December 1994 was performed. All patients underwent the surgical removal of subfoveal choroidal neovascularization due to POHS and had at least 3 months of follow-up. Postoperative Snellen visual acuity was the primary study endpoint. RESULTS: With a median follow-up of 13 months (range, 3-46 months), 35% of patients had postoperative visual acuity of 20/40 or better, and 40% had improvement of three or more Snellen lines after surgery. In a subset of 54 eyes followed for at least 1 year, 91% showed stable or improved vision between the 3- and 12-month time points, and 85% showed stable or improved vision between 3 months and final visit. CONCLUSION: Follow-up of a large number of patients appears to confirm initially encouraging results and to suggest stability of beneficial effect after the surgical removal of subfoveal choroidal neovascularization in POHS.

Managing recurrent neovascularization after subfoveal surgery in presumed ocular histoplasmosis syndrome.

PURPOSE: To report the authors' experience with recurrent neovascularization after subfoveal surgery in the presumed ocular histoplasmosis syndrome (POHS). METHODS: One-hundred seventeen patients with POHS and subfoveal choroidal neovascularization were followed a median of 13 months after submacular surgery. RESULTS: Recurrent neovascularization developed in 51 eyes (44%). The median time to recurrence was 3 months (range, 0.5-28 months). Recurrence location was extrafoveal in 16%, juxtafoveal in 18%, and subfoveal in 66%. Sixteen eyes were treated with laser photocoagulation, 17 eyes underwent repeat submacular surgery, and 18 eyes were observed. The visual outcome for patients with recurrences amenable to laser was better than that for patients who were observed or who underwent surgery. CONCLUSION: Recurrent neovascularization after surgery is common; prompt recognition may allow laser photocoagulation.

Visual results after surgical removal of subfoveal choroidal neovascular membranes.

PURPOSE: The authors report their experience with the surgical removal of subfoveal choroidal neovascularization. Correlations between preoperative characteristics and final postoperative visual acuity are explored. METHODS: A retrospective study of 159 consecutive patients was performed between February 1990 and August 1993. Follow-up of 2 or more months was available for 147 eyes: presumed ocular histoplasmosis syndrome, 67 eyes; age-related macular degeneration, 41 eyes; myopia, 10 eyes; multifocal choroiditis, 9 eyes; idiopathic, 8 eyes; angioid streaks, 4 eyes; and miscellaneous, 8 eyes. RESULTS: Sixty-seven eyes had presumed ocular histoplasmosis syndrome: mean follow-up was 10.5 months. Visual acuity was stable or improved in 56 (83%) eyes and 20/40 or greater in 21 (31%) eyes. Mean interval to best visual acuity was 3 months. A recurrence rate of 37% had no significant effect on final visual outcome (P = 0.952). Forty-one eyes had age-related macular degeneration: mean follow-up was 15 months. Visual acuity was improved in only five (12%) eyes and was 20/40 or greater in only two (5%) eyes. The interval to best visual acuity was 5 months. A recurrence rate of 27% had not significant effect on final visual outcome (P = 0.31). The visual results and recurrence rates for eyes with less common disorders are presented. CONCLUSION: The surgical excision of subfoveal choroidal neovascularization may stabilize or improve visual acuity in selected cases. Patients with focal disorders of the retinal pigment epithelium-Bruch's membrane complex appear to have a better surgical outcome than those with diffuse disease.