Clinical investigations of TGF-b in OME showed its relation to chronic otitis media. 105, 106 The identification of TGF-b in serous and mucoid middle ear effusions was associated with a history of previous tympanostomy tube placements. 105 Investigation of growth factors in tympanic membrane perforations showed that TGF-b could promote development of the fibrotic scar at the perforation margin, explaining the deficient healing pattern of tympanic membranes in chronic otitis media. 106 However studies of cytokines in experimental OME demonstrated the presence of TGF-b also in acute otitis media. 100, 102, 103 The expression of TGF-b mRNA was up-regulated in acute otitis media caused by S. pneumoniae 100, 102 and NTHi infections, 102, 103 and was detected early during the course of acute inflammation, within 24 h after inoculation, together with cytokines IL-1, TNF-a and IL-10. However, the highest mRNA levels for TGF-b were recorded considerably later, on days 6 and 28, for the NTHiinfected and pneumococcus-infected animals, respectively, and its expression continued even after resolution of acute otitis media. 102 TGF-b regulates host response in infectious diseases through the TGF-b-activated kinase 1 107 and TGF-b-Smad signaling pathway. 108 It has been shown that NTHi, a major human bacterial pathogen of otitis media, strongly induced up-regulation of MUC5AC mucin in human epithelial cells. This induction occurred via activation of the Toll-like receptor 2-MyD88-dependent p38 mitogen-activated protein kinase (MAPK) pathway. However, activation of TGF-b-Smad signaling by TGF-b resulted in downregulation of p38 MAPK by inducing MAPK phophatase-1, and subsequent down-regulation of MUC5AC transcription. 108 TGF-b thereby acted as a negative regulator of MUC5AC mucin gene expression. This is a very significant fact in understanding the role of TGF-b in otitis media, because varying levels of the secreted mucin MUC5AC are presented in the middle ear mucosa and effusions in patients with OME. 53, 55, 57 By analysis of these data we can make the following conclusions about the role of TGF-b in OME: