Studies on the mechanism of PUVA and UVB-induced cutaneous inflammatory reactions and their modulations by potential chemotherapeutic agents in vivo

A rabbit model was established to study the cutaneous phototoxic inflammatory reactions induced by topical application of 8-methoxypsorlen (8-MOP) on irradiation (320-700 nm) and ultraviolet B (280-320 nm), commonly known as PUVA and UVB therapies respectively. Three parameters of inflammatory responses were quantitated namely (a) increase in vascular permeability (iVP), (b) migration and accumulation of polymorphonuclear leucocytes (aPMN), and (c) erythema formation in situ. Increase in VP and aPMN were quantitated using $\sp{125}$I-albumin and $\sp{51}$Cr-labelled PMNs respectively. Erythema was graded visually. PUVA induced iVP, aPMN and erythema formation were not measurable until 6 h post-irradiation, reached a maximum in 24 h and gradually subsided 72 h after irradiation, however, erythema was still perceptible at that time. The response was 8-MOP concentration and irradiation-dose dependent. Mast cells were not found essential for the initiation of the reactions. On irradiation, Rose bengal (RB) injected sites produced iVP and aPMN response (without erythema) within 3 h of irradiation and gradually subsided in 12 hrs (type II reaction). A "tolerant/unresponsive/desensitized" state developed on repeated irradiation of 8-MOP applied or RB injected skin sites. The sites that developed tolerance by repeated irradiation after 8-MOP application were also tolerant to RB on irradiation, Similarly, the sites made tolerant by repeated irradiation after RB injection showed unresponsiveness to 8-MOP on irradiation. These results suggest that there are some common components involved in the establishment of tolerant/unresponsive state in 8-MOP (type I) and RB (type II) reactions. Phospholipase A$\sb2,$ cyclooxygenase and lipoxygenase seem to play a significant role in PUVA-induced inflammatory reactions. UVB-induced inflammation was also of delayed nature and dose-dependent. In this reaction, erythema became perceptible first at 6 h after irradiation which reached maximum in 24 h and in contrast to PUVA induced reaction, it gradually culminated into non-blanching brownish red colour observable even after 6 days. The aPMN and iVP responses peaked at 6 and 24 h post-irradiation respectively which subsided gradually over 72 h but unlike PUVA induced reactions the rate of aPMN response was more than the respective controls even after 6 days. Like PUVA reactions, mast cells did not play a role in initiation of UVB-induced reactions. Nitric oxide synthase, cyclooxygenase and lipoxygenase seem to be involved in UVB-induced inflammation. These results suggest that PUVA induced delayed reactions (type I) hallmarked with erythema are different from RB-induced (type II) reactions which appear immediately and without erythema formation. The nature and course of inflammatory reactions induced by PUVA and UVB are different from each other. Furthermore, the dissociation of iVP, aPMN and erythemal responses from each other is suggestive of involvement of more than one mediator(s) both in PUVA and UVB induced inflammatory reactions.